Amino acid derived prodrugs of propofol, compositions and uses thereof

ABSTRACT

The present invention provides propofol prodrugs, methods of making propofol prodrugs, pharmaceutical compositions of propofol prodrugs and methods of using propofol prodrugs and pharmaceutical compositions thereof to treat or prevent diseases or disorders such as migraine headache pain and post-chemotherapy or post-operative surgery nausea and vomiting.

This application claims the benefit under 35 U.S.C. § 119(e) of U.S.Provisional Application Ser. No. 60/443,315, filed Jan. 28, 2003. Theabove application is incorporated herein by reference in their entirety.

1. TECHNICAL FIELD

The present invention provides propofol prodrugs, methods of makingpropofol prodrugs, pharmaceutical compositions of propofol prodrugs andmethods of using propofol prodrugs and pharmaceutical compositionsthereof to treat or prevent diseases or disorders such as migraineheadache pain and post-chemotherapy or post-operative surgery nausea andvomiting.

2. BACKGROUND ART

Propofol (2,6-diisopropylphenol), (1), is a low molecular weight phenolthat is widely used as an intravenous sedative-hypnotic agent in theinduction and maintenance of anesthesia and/or sedation in mammals. Theadvantages of propofol as an anesthetic include rapid onset ofanesthesia, rapid clearance, and minimal side effects (Langley et al.,Drugs 1988, 35, 334–372). Propofol may mediate hypnotic effects throughinteraction with the GABA_(A) receptor complex, a hetero-oligomericligand-gated chloride ion channel (Peduto et al., Anesthesiology 1991,75, 1000–1009.).

Propofol is rapidly metabolized in mammals with the drug beingeliminated predominantly as glucuronidated and sulfated conjugates ofpropofol and 4-hydroxypropofol (Langley et al., Drugs 1988, 35,334–372). Propofol clearance exceeds liver blood flow, which indicatesthat extrahepatic tissues contribute to the overall metabolism of thedrug. Human intestinal mucosa glucuronidates propofol in vitro and oraldosing studies in rats indicate that approximately 90% of theadministered drug undergoes first pass metabolism, with extraction bythe intestinal mucosa accounting for the bulk of this presystemicelimination (Raoof et al., Pharm. Res. 1996, 13, 891–895). Because ofits extensive first-pass metabolism, propofol is administered byinjection or intravenous infusion and oral administration has not beenconsidered therapeutically effective.

Propofol has a broad range of biological and medical applications, whichare evident at sub-anesthetic doses and include treatment and/orprevention of intractable migraine headache pain (Krusz et al., Headache2000, 40, 224–230; Krusz, International Publication No. WO 00/54588).Propofol, when used to maintain anesthesia, causes a lower incidence ofpost-operative nausea and vomiting (“PONV”) when compared to commoninhalation anesthetic agents and numerous controlled clinical studiessupport the anti-emetic activity of propofol (Tramer et al., Br. J.Anaesth. 1997, 78, 247–255; Brooker et al., Anaesth. Intensive Care1998, 26, 625–629; Gan et al., Anesthesiology 1997, 87, 779–784).Propofol has also been shown to have anti-emetic activity when used inconjunction with chemotherapeutic compounds (Phelps et al., Ann.Pharmacother. 1996, 30, 290–292; Borgeat et al., Oncology 1993, 50,456–459; Borgeat et al., Can. J. Anaesth. 1994, 41, 1117–1119; Tomiokaet al., Anesth. Analg. 1999, 89, 798–799). Nausea, retching and/orvomiting induced by a variety of chemotherapeutic agents (e.g.,cisplatin, cyclophosphamide, 5-fluorouracil, methotrexate, anthracyclinedrugs, etc.) has been controlled by low-dose propofol infusion inpatients refractory to prophylaxis with conventional anti-emetic drugs(e.g., serotonin antagonists and corticosteroids).

Propofol has also been used to treat patients with refractory statusepilepticus (Brown et al., Pharmacother. 1998, 32, 1053–1059; Kuisma etal., Epilepsia 1995, 36, 1241–1243; Walder et al., Neurology 2002, 58,1327–1332; Sutherland et al., Anaesth. Intensive Care 1994, 22,733–737). Further, the anticonvulsant effects of propofol have also beendemonstrated in rat efficacy models at sub-anesthetic doses (Holtkamp etal., Ann. Neurol. 2001, 49, 260–263; Hasan et al., Pharmacol. Toxicol.1994, 74, 50–53).

Propofol has also been used as an antioxidant (Murphy et al., Br. J.Anaesth. 1992, 68, 613–618; Sagara et al., J. Neurochem. 1999, 73,2524–2530; Young et al., Eur. J. Anaesthesiol. 1997, 14, 320–326; Wanget al. Eur. J. Pharmacol. 2002, 452, 303–308). Propofol, at dosestypically used for surgical anesthesia, has observable antioxidanteffects in humans (De la Cruz et al., Anesth. Analg. 1999, 89,1050–1055). Pathogenesis or subsequent damage pathways in variousneurodegenerative diseases involve reactive oxygen species andaccordingly may be treated or prevented with antioxidants (Simonian etal., Pharmacol. Toxicol. 1996, 36, 83–106). Examples of specificneurodegenerative diseases which may be treated or prevented withanti-oxidants include, but are not limited to, Friedrich's disease,Parkinson's disease, Alzheimer's disease, Huntington's disease,amyotrophic lateral sclerosis (“ALS”), multiple sclerosis (“MS”), Pickdisease, inflammatory diseases and diseases caused by inflammatorymediators such as tumor necrosis factor (TNF) and IL-1.

A significant problem with the formulation and use of propofol is poorwater solubility. Accordingly, propofol must be specially formulated inaqueous media using solubilizers or emulsifiers (Briggs et al.,Anaesthesia 1982, 37, 1099–1101). For Example, in a current commercialproduct (Diprivan®, Astra-Zeneca) an oil-in-water emulsion (theemulsifier is the lecithin mixture Intralipid®), is used to formulatepropofol (Picard et al., Anesth. Analg. 2000, 90, 963–969).Unfortunately, the oil-in-water emulsion formulation causes discomfortand pain at the site of injection.

One potential solution to the poor water solubility of propofol whichavoids the use of additives, solubilizers or emulsifiers and theattendant injection site pain, is a water-soluble, stable propofolprodrug that is converted to propofol in vivo. (Hendler et al.,International Publication No. WO 99/58555; Morimoto et al.,International Publication No. WO 00/48572; Hendler et al., U.S. Pat. No.6,254,853; Stella et al., United States Patent Application No.US2001/0025035; Hendler, U.S. Pat. No. 6,362,234; Hendler, InternationalPublication No. WO 02/13810; Sagara et al., J. Neurochem. 1999, 73,2524–2530; Banaszczyk et al., Anesth. Analg. 2002, 95, 1285–1292;Trapani et al., Int. J. Pharm. 1998, 175, 195–204; Trapani et al., J.Med. Chem. 1998, 41, 1846–1854; Anderson et al., J. Med. Chem. 2001, 44,3582–3591; Pop et al., Med. Chem. Res. 1992, 2, 16–21). A significantproblem with these existing propofol prodrugs is their high stability invivo. This stability prevents release of therapeutically significantconcentrations of propofol, particularly when the prodrug is orallyadministered.

Accordingly, there is a need for propofol prodrugs, which aresufficiently labile under physiological conditions to providetherapeutically effective concentrations of propofol, particularly, whenthe prodrug is orally administered.

3. SUMMARY

Disclosed herein are propofol prodrugs, methods of making propofolprodrugs, pharmaceutical compositions of propofol prodrugs and methodsof using propofol prodrugs to treat or prevent diseases or disorderssuch as migraine headache pain, neurodegenerative disorders andpost-chemotherapy or post-operative surgery nausea and vomiting whichsatisfies the above need. In one embodiment, prodrugs of propofol andpharmaceutical compositions thereof are orally administered. In anotherembodiment, prodrugs of propofol are translocated across thegastrointestinal mucosa via interaction with transporter proteinsexpressed within enterocytes lining the gastrointestinal tract.

In a first aspect, a compound of structural Formula (I) is provided:

or a pharmaceutically acceptable salt, hydrate, solvate or N-oxidethereof, wherein:

X is selected from the group consisting of a bond, —CH₂—, —NR¹¹—, —O—and —S—;

m is 1 or 2;

n is 0 or 1;

R¹ is selected from the group consisting of hydrogen,[R⁵NH(CHR⁴)_(p)C(O)]—, R⁶—, R⁶C(O)— and R⁶OC(O)—;

R² is —OR⁷ or —[NR⁸(CHR⁹)_(q)C(O)OR⁷];

p and q are independently 1 or 2;

R³ is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkoxycarbonyl, aryl, substituted aryl, arylalkyl, carbamoyl,substituted carbamoyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, heteroaryl, substituted heteroaryl andheteroarylalkyl;

each R⁴ is independently selected from the group consisting of hydrogen,alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, substitutedacyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substitutedaryl, arylalkyl, substituted arylalkyl, carbamoyl, substitutedcarbamoyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl and substitutedheteroarylalkyl, or optionally, when R⁴ and R⁵ are attached to adjacentatoms then R⁴ and R⁵ together with the atoms to which they are bondedform a cycloheteroalkyl or substituted cycloheteroalkyl ring;

R⁵ is selected from the group consisting of hydrogen, R⁶—, R⁶C(O)— andR⁶OC(O)—;

R⁶ is selected from the group consisting of alkyl, substituted alkyl,aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, heteroaryl, substitutedheteroaryl and heteroarylalkyl;

R⁷ is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl,cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, heteroaryl,substituted heteroaryl and heteroarylalkyl;

R⁸ is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, aryl, substituted aryl, arylalkyl, cycloalkyl, substitutedcycloalkyl, cycloheteroalkyl, heteroaryl, substituted heteroaryl andheteroarylalkyl;

each R⁹ is independently selected from the group consisting of hydrogen,alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, substitutedacyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substitutedaryl, arylalkyl, substituted arylalkyl, carbamoyl, substitutedcarbamoyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl and substitutedheteroarylalkyl, or optionally, when R⁸ and R⁹ are attached to adjacentatoms then R⁸ and R⁹ together with the atoms to which they are bondedform a cycloheteroalkyl or substituted cycloheteroalkyl ring;

R¹¹ is selected from the group consisting of hydrogen, alkyl,substituted alkyl, aryl, substituted aryl, arylalkyl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, heteroaryl, substitutedheteroaryl and heteroarylalkyl;

with the provisos that:

when R¹ is [R⁵NH(CHR⁴)_(p)C(O)]— then R² is —OR⁷;

and when R² is —[NR⁸(CHR⁹)_(q)C(O)OR⁷] then R¹ is not[R⁵NH(CHR⁴)_(p)C(O)]—.

In a another aspect, a compound of structural Formula (II) is provided:

or a pharmaceutically acceptable salt, hydrate, solvate or N-oxidethereof, wherein:

R¹⁰ is hydrogen or [R⁵NH(CHR⁴)_(p)C(O)]—;

n is 0 or 1;

p and q are independently 1 or 2;

each of R³, R⁴, R⁵, R⁸ and R⁹ is as described above;

with the proviso that when R¹⁰ is hydrogen then n is 1.

In still another aspect, pharmaceutical compositions are provided. Thepharmaceutical compositions disclosed herein generally comprise one ormore compounds of Formulae (I)–(XVIII), and a pharmaceuticallyacceptable vehicle such as a diluent, carrier, excipient or adjuvant.The choice of diluent, carrier, excipient and adjuvant will depend upon,among other factors, the desired mode of administration. In oneembodiment, the mode of administration is oral.

In still another aspect, methods for treating various diseases ordisorders are provided. The methods disclosed herein generally compriseadministering one or more compounds of Formulae (I)–(XVIII) in order toachieve a therapeutically effective concentration of propofol in theblood and/or tissue of a patient. The methods are useful for treating orpreventing diseases or disorders including, but not limited to, migraineheadache pain, post-chemotherapy or post-operative surgery nausea andvomiting and neurodegenerative disorders (e.g., epilepsy, Friedrich'sdisease, Parkinson's disease, Alzheimer's disease, Huntington's disease,amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Pickdisease, etc.). The methods generally involve administering to a patientin need of such treatment or prevention a therapeutically effectiveamount of one or more compounds of Formulae (I)–(XVIII), orpharmaceutical composition containing one or more compounds of Formulae(I)–(XVIII).

In still another aspect, methods for inducing and/or maintaininganesthesia or sedation in a mammal are provided. The methods generallyinvolve administering to a patient in need of such anesthesia orsedation induction and/or maintenance a therapeutically effective amountof one or more compounds of Formulae (I)–(XVIII), or pharmaceuticalcomposition containing one or more compounds of Formulae (I)–(XVIII).

4. DETAILED DESCRIPTION 4.1 Definitions

“Alkyl” by itself or as part of another substituent refers to asaturated or unsaturated, branched, straight-chain or cyclic monovalenthydrocarbon radical derived by the removal of one hydrogen atom from asingle carbon atom of a parent alkane, alkene or alkyne. Typical alkylgroups include, but are not limited to, methyl; ethyls such as ethanyl,ethenyl, ethynyl; propyls such as propan-1-yl, propan-2-yl,cyclopropan-1-yl, prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl(allyl), cycloprop-1-en-1-yl; cycloprop-2-en-1-yl, prop-1-yn-1-yl,prop-2-yn-1-yl, etc.; butyls such as butan-1-yl, butan-2-yl,2-methyl-propan-1-yl, 2-methyl-propan-2-yl, cyclobutan-1-yl,but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl,but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl,cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl,but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like.

The term “alkyl” is specifically intended to include groups having anydegree or level of saturation, i.e., groups having exclusively singlecarbon-carbon bonds, groups having one or more double carbon-carbonbonds, groups having one or more triple carbon-carbon bonds and groupshaving mixtures of single, double and triple carbon-carbon bonds. Wherea specific level of saturation is intended, the expressions “alkanyl,”“alkenyl,” and “alkynyl” are used. Preferably, an alkyl group comprisesfrom 1 to 20 carbon atoms, more preferably, from 1 to 10 carbon atoms,even more preferably, 1 to 6 carbon atoms. “C₁₋₆ alkyl” refers to analkyl group containing from 1 to 6 carbon atoms.

“Alkanyl” by itself or as part of another substituent refers to asaturated branched, straight-chain or cyclic alkyl radical derived bythe removal of one hydrogen atom from a single carbon atom of a parentalkane. Typical alkanyl groups include, but are not limited to,methanyl; ethanyl; propanyls such as propan-1-yl, propan-2-yl(isopropyl), cyclopropan-1-yl, etc.; butanyls such as butan-1-yl,butan-2-yl (sec-butyl), 2-methyl-propan-1-yl (isobutyl),2-methyl-propan-2-yl (t-butyl), cyclobutan-1-yl, etc.; and the like.

“Alkenyl” by itself or as part of another substituent refers to anunsaturated branched, straight-chain or cyclic alkyl radical having atleast one carbon-carbon double bond derived by the removal of onehydrogen atom from a single carbon atom of a parent alkene. The groupmay be in either the cis or trans conformation about the double bond(s).Typical alkenyl groups include, but are not limited to, ethenyl;propenyls such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl(allyl), prop-2-en-2-yl, cycloprop-1-en-1-yl; cycloprop-2-en-1-yl;butenyls such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl,but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl,buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl,cyclobuta-1,3-dien-1-yl, etc.; and the like.

“Alkynyl” by itself or as part of another substituent refers to anunsaturated branched, straight-chain or cyclic alkyl radical having atleast one carbon-carbon triple bond derived by the removal of onehydrogen atom from a single carbon atom of a parent alkyne. Typicalalkynyl groups include, but are not limited to, ethynyl; propynyls suchas prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butynyls such as but-1-yn-1-yl,but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like.

“Acyl” by itself or as part of another substituent refers to a radical—C(O)R³⁰, where R³⁰ is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl,aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl as definedherein. Representative Examples include, but are not limited to formyl,acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl,benzylcarbonyl and the like.

“Alkoxy” by itself or as part of another substituent refers to a radical—OR³¹ where R³¹ represents an alkyl or cycloalkyl group as definedherein. Representative examples include, but are not limited to,methoxy, ethoxy, propoxy, butoxy, cyclohexyloxy and the like.

“Alkoxycarbonyl” by itself or as part of another substituent, refers toa radical —C(O)OR³¹ where R³¹ is as defined above.

“Aryl” by itself or as part of another substituent refers to amonovalent aromatic hydrocarbon radical derived by the removal of onehydrogen atom from a single carbon atom of a parent aromatic ringsystem. Typical aryl groups include, but are not limited to, groupsderived from aceanthrylene, acenaphthylene, acephenanthrylene,anthracene, azulene, benzene, chrysenei, coronene, fluoranthene,fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene,indane, indene, naphthalene, octacene, octaphene, octalene, ovalene,penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene,phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene,triphenylene, trinaphthalene and the like. Preferably, an aryl groupcomprises from 6 to 20 carbon atoms, more preferably, from 6 to 12carbon atoms.

“Arylalkyl” by itself or as part of another substituent refers to anacyclic alkyl radical in which one of the hydrogen atoms bonded to acarbon atom, typically a terminal or sp³ carbon atom, is replaced withan aryl group. Typical arylalkyl groups include, but are not limited to,benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl,2-naphthylethan-1-yl, 2-naphthylethen-1-yl, naphthobenzyl,2-naphthophenylethan-1-yl and the like. Where specific alkyl moietiesare intended, the nomenclature arylalkanyl, arylalkenyl and/orarylalkynyl is used. Preferably, an arylalkyl group is (C₆–C₃₀)arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the arylalkylgroup is (C₁–C₁₀) and the aryl moiety is (C₆–C₂₀), more preferably, anarylalkyl group is (C₆–C₂₀) arylalkyl, e.g., the alkanyl, alkenyl oralkynyl moiety of the arylalkyl group is (C₁–C₈) and the aryl moiety is(C₆–C₁₂).

“Carbamoyl” by itself or as part of another substituent refers to theradical —C(O)N(R³²)R³³ where R³² and R³³ are independently hydrogen,alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl orsubstituted heteroaryl, as defined herein.

“Compounds” as used herein refer to compounds encompassed by the genericformulae disclosed herein and include any specific compounds withinthose formulae whose structure is disclosed herein. The compounds may beidentified either by their chemical structure and/or chemical name. Whenthe chemical structure and chemical name conflict, the chemicalstructure is determinative of the identity of the compound. Thecompounds may contain one or more chiral centers and/or double bonds andtherefore, may exist as stereoisomers, such as double-bond isomers(i.e., geometric isomers), enantiomers or diastereomers. Accordingly,when stereochemistry at chiral centers is not specified, the chemicalstructures depicted herein encompass all possible configurations atthose chiral centers including the stereoisomerically pure form (e.g.,geometrically pure, enantiomerically pure or diastereomerically pure)and enantiomeric and stereoisomeric mixtures. Enantiomeric andstereoisomeric mixtures can be resolved into their component enantiomersor stereoisomers using separation techniques or chiral synthesistechniques well known to the skilled artisan. The compounds may alsoexist in several tautomeric forms including the enol form, the keto formand mixtures thereof. Accordingly, the chemical structures depictedherein encompass all possible tautomeric forms of the illustratedcompounds. The compounds also include isotopically labeled compoundswhere one or more atoms have an atomic mass different from the atomicmass conventionally found in nature. Examples of isotopes that may beincorporated into the compounds include, but are not limited to, ²H, ³H,¹³C, ¹⁴C, ¹⁵N, ¹⁷O, and ¹⁸O. Compounds may exist in unsolvated forms aswell as solvated forms, including hydrated forms and as N-oxides. Ingeneral, the hydrated, solvated and N-oxide forms are within the scopeof the present invention. Certain compounds may exist in multiplecrystalline or amorphous forms. In general, all physical forms areequivalent for the uses contemplated herein and are intended to bewithin the scope of the present disclosure. Further, it should beunderstood, when partial structures of the compounds are illustrated,that brackets indicate the point of attachment of the partial structureto the rest of the molecule.

“Cycloalkyl” by itself or as part of another substituent refers to asaturated or unsaturated cyclic alkyl radical. Where a specific level ofsaturation is intended, the nomenclature “cycloalkanyl” or“cycloalkenyl” is used. Typical cycloalkyl groups include, but are notlimited to, groups derived from cyclopropane, cyclobutane, cyclopentane,cyclohexane, and the like. Preferably, the cycloalkyl group is (C₃–C₁₀)cycloalkyl, more preferably, (C₃–C₇) cycloalkyl.

“Cycloheteroalkyl” by itself or as part of another substituent refers toa saturated or unsaturated cyclic alkyl radical in which one or morecarbon atoms (and any associated hydrogen atoms) are independentlyreplaced with the same or different heteroatom. Typical heteroatoms toreplace the carbon atom(s) include, but are not limited to, N, P, O, S,Si, etc. Where a specific level of saturation is intended, thenomenclature “cycloheteroalkanyl” or “cycloheteroalkenyl” is used.Typical cycloheteroalkyl groups include, but are not limited to, groupsderived from epoxides, azirines, thiiranes, imidazolidine, morpholine,piperazine, piperidine, pyrazolidine, pyrrolidine, quinuclidine and thelike.

“Heteroalkyl, Heteroalkanyl Heteroalkenyl and Heteroalkynyl” bythemselves or as part of another substituent refer to alkyl, alkanyl,alkenyl and alkynyl groups, respectively, in which one or more of thecarbon atoms (and any associated hydrogen atoms) are independentlyreplaced with the same or different heteroatomic groups. Typicalheteroatomic groups which can be included in these groups include, butare not limited to, —O—, —S—, —O—O—, —S—S—, —O—S—, —NR³⁴R³⁵—, ═N—N═,—N═N—, —N═N—NR³⁶R³⁷, —PR³⁸—, —P(O)₂—, —POR³⁹—, —O—P(O)₂—, —SO—, —SO₂—,—SnR⁴⁰R⁴¹— and the like, where R³⁴, R³⁵, R³⁶, R³⁷, R³⁸, R³⁹, R⁴⁰ and R⁴¹are independently hydrogen, alkyl, substituted alkyl, aryl, substitutedaryl, arylalkyl, substituted arylalkyl, cycloalkyl, substitutedcycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl,substituted heteroalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl or substituted heteroarylalkyl.

“Heteroaryl” by itself or as part of another substituent refers to amonovalent heteroaromatic radical derived by the removal of one hydrogenatom from a single atom of a parent heteroaromatic ring system. Typicalheteroaryl groups include, but are not limited to, groups derived fromacridine, arsindole, carbazole, β-carboline, chromane, chromene,cinnoline, furan, imidazole, indazole, indole, indoline, indolizine,isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline,isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine,phenanthridine, phenanthroline, phenazine, phthalazine, pteridine,purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine,pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline,tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and thelike. Preferably, the heteroaryl group is from 5–20 membered heteroaryl,more preferably from 5–10 membered heteroaryl. Preferred heteroarylgroups are those derived from thiophene, pyrrole, benzothiophene,benzofuran, indole, pyridine, quinoline, imidazole, oxazole andpyrazine.

“Heteroarylalkyl” by itself or as part of another substituent refers toan acyclic alkyl radical in which one of the hydrogen atoms bonded to acarbon atom, typically a terminal or sp³ carbon atom, is replaced with aheteroaryl group. Where specific alkyl moieties are intended, thenomenclature heteroarylalkanyl, heteroarylalkenyl and/orheterorylalkynyl is used. In preferred embodiments, the heteroarylalkylgroup is a 6–30 membered heteroarylalkyl, e.g., the alkanyl, alkenyl oralkynyl moiety of the heteroarylalkyl is 1–10 membered and theheteroaryl moiety is a 5–20-membered heteroaryl, more preferably, 6–20membered heteroarylalkyl, e.g., the alkanyl, alkenyl or alkynyl moietyof the heteroarylalkyl is 1–8 membered and the heteroaryl moiety is a5–12-membered heteroaryl.

“Parent Aromatic Ring System” refers to an unsaturated cyclic orpolycyclic ring system having a conjugated π electron system.Specifically included within the definition of “parent aromatic ringsystem” are fused ring systems in which one or more of the rings arearomatic and one or more of the rings are saturated or unsaturated, suchas, for Example, fluorene, indane, indene, phenalene, etc. Typicalaromatic ring systems include, but are not limited to, aceanthrylene,acenaphthylene, acephenanthrylene, anthracene, azulene, benzene,chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene,hexalene, as-indacene, s-indacene, indane, indene, naphthalene,octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene,pentalene, pentaphene, perylene, phenalene, phenanthrene, picene,pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthaleneand the like.

“Parent Heteroaromatic Ring System” refers to an aromatic ring system inwhich one or more carbon atoms (and any associated hydrogen atoms) areindependently replaced with the same or different heteroatom. Typicalheteroatoms to replace the carbon atoms include, but are not limited to,N, P, O, S, Si, etc. Specifically included within the definition of“parent heteroaromatic ring systems” are fused ring systems in which oneor more of the rings are aromatic and one or more of the rings aresaturated or unsaturated, such as, for Example, arsindole, benzodioxan,benzofuran, chromane, chromene, indole, indoline, xanthene, etc. Typicalheteroaromatic ring systems include, but are not limited to, arsindole,carbazole, β-carboline, chromane, chromene, cinnoline, furan, imidazole,indazole, indole, indoline, indolizine, isobenzofuran, isochromene,isoindole, isoindoline, isoquinoline, isothiazole, isoxazole,naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine,phenanthroline, phenazine, phthalazine, pteridine, purine, pyran,pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole,pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline,tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and thelike.

“Pharmaceutical composition” refers to at least one compound of Formulae(I) or (II) and a pharmaceutically acceptable vehicle, with which thecompound is administered to a patient.

“Pharmaceutically acceptable salt” refers to a salt of a compound ofFormulae (I) or (II), which possesses the desired pharmacologicalactivity of the parent compound. Such salts include: (1) acid additionsalts, formed with inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and thelike; or formed with organic acids such as acetic acid, propionic acid,hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid,lactic acid, malonic acid, succinic acid, malic acid, maleic acid,fumaric acid, tartaric acid, citric acid, benzoic acid,3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like; or (2)salts formed when an acidic proton present in the parent compound isreplaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, N-methylglucamine and thelike.

“Pharmaceutically acceptable vehicle” refers to a diluent, adjuvant,excipient or carrier with which a compound of Formulae (I) or (II) isadministered.

“Patient” includes humans. The terms “human” and “patient” are usedinterchangeably herein.

“PEPT1” refers to an oligopeptide transporter protein that normallyabsorbs dipeptides and tripeptides (and related structures) in certaintissues, such as the intestine (Adibi, S. A., Gastroenterology 1997,113, 332–340; Leibach et al., Ann. Rev. Nutr. 1996, 16, 99–119).

“Preventing” or “prevention” refers to a reduction in risk of acquiringa disease or disorder (i.e., causing at least one of the clinicalsymptoms of the disease not to develop in a patient that may be exposedto or predisposed to the disease but does not yet experience or displaysymptoms of the disease).

“Prodrug” refers to a derivative of a drug molecule that requires atransformation within the body to release the active drug. Prodrugs arefrequently, although not necessarily, pharmacologically inactive untilconverted to the parent drug. A hydroxyl containing drug may beconverted to, for Example, to an ester, carbonate, acyloxyalkyl or asulfonate prodrug, which may be hydrolyzed in vivo to provide thehydroxyl compound. Prodrugs for drugs which functional groups differentthan those listed above are well known to the skilled artisan.

“Promoiety” refers to a form of protecting group that when used to maska functional group within a drug molecule converts the drug into aprodrug. Typically, the promoiety will be attached to the drug viabond(s) that are cleaved by enzymatic or non-enzymatic means in vivo.

“Protecting group” refers to a grouping of atoms that when attached to areactive functional group in a molecule masks, reduces or preventsreactivity of the functional group. Examples of protecting groups can befound in Green et al., “Protective Groups in Organic Chemistry”, (Wiley,2^(nd) ed. 1991) and Harrison et al., “Compendium of Synthetic OrganicMethods”, Vols. 1–8 (John Wiley and Sons, 1971–1996). Representativeamino protecting groups include, but are not limited to, formyl, acetyl,trifluoroacetyl, benzyl, benzyloxycarbonyl (“CBz”), tert-butoxycarbonyl(“Boc”), trimethylsilyl (“TMS”), 2-trimethylsilyl-ethanesulfonyl(“SES”), trityl and substituted trityl groups, allyloxycarbonyl,9-fluorenylmethyloxycarbonyl (“FMOC”), nitro-veratryloxycarbonyl(“NVOC”) and the like. Representative hydroxy protecting groups include,but are not limited to, those where the hydroxy group is either acylatedor alkylated such as benzyl, and trityl ethers as well as alkyl ethers,tetrahydropyranyl ethers, trialkylsilyl ethers and allyl ethers.

“Substituted” refers to a group in which one or more hydrogen atoms areindependently replaced with the same or different substituent(s).Typical substituents include, but are not limited to, -M, —R⁶⁰, —O⁻, ═O,—OR⁶⁰, —SR⁶⁰, —S⁻, ═S, —NR⁶⁰R⁶¹ , ═NR⁶⁰, —CF₃, —CN, —OCN, —SCN, —NO,—NO₂, ═N₂, —N₃, —S(O)₂O⁻, —S(O)₂OH, —S(O)₂R⁶⁰, —OS(O₂)O⁻, —OS(O)₂R⁶⁰,—P(O)(O⁻)₂, —P(O)(OR⁶⁰)(O⁻), —OP(O)(OR⁶⁰)(OR⁶¹), —C(O)R⁶⁰, —C(S)R⁶⁰,—C(O)OR⁶⁰, —C(O)NR⁶⁰R⁶¹, —C(O)O⁻, —C(S)OR⁶⁰, —NR⁶²C(O)NR⁶⁰R⁶¹,—NR⁶²C(S)NR⁶⁰R⁶¹, —NR⁶²C(NR⁶³)NR⁶⁰R⁶¹ and —C(NR⁶²)NR⁶⁰R⁶¹ where M isindependently a halogen; R⁶¹, R⁶⁰R⁶² and R⁶³ are independently hydrogen,alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,aryl, substituted aryl, heteroaryl or substituted heteroaryl, oroptionally R⁶⁰ and R⁶¹ together with the nitrogen atom to which they arebonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; andR⁶⁴ and R⁶⁵ are independently hydrogen, alkyl, substituted alkyl, aryl,cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substitutedcycloheteroalkyl, aryl, substituted aryl, heteroaryl or substitutedheteroaryl, or optionally R⁶⁴ and R⁶⁵ together with the nitrogen atom towhich they are bonded form a cycloheteroalkyl or substitutedcycloheteroalkyl ring. Preferably, substituents include -M, —R⁶⁰, ═O,—OR⁶⁰, —SR⁶⁰, —S⁻, ═S, —NR⁶⁰R⁶¹, ═NR⁶⁰, —CF₃, —CN, —OCN, —SCN, —NO,—NO₂, ═N₂, —N₃, —S(O)₂R⁶⁰, —OS(O₂)O⁻, —OS(O)₂R⁶⁰, —P(O)(O⁻)₂,—P(O)(OR⁶⁰)(O⁻), —OP(O)(OR⁶⁰)(OR⁶¹), —C(O)R⁶⁰, —C(S)R⁶⁰, —C(O)OR⁶⁰,—C(O)NR⁶⁰R⁶¹, —C(O)O⁻, —NR⁶²C(O)NR⁶⁰R⁶¹, more preferably, -M, —R⁶⁰, ═O,—OR⁶⁰, —SR⁶⁰, —NR⁶⁰R⁶¹, —CF₃, —CN, —NO₂, —S(O)₂R⁶⁰, —P(O)(OR⁶⁰)(O⁻),—OP(O)(OR⁶⁰)(OR⁶¹), —C(O)R⁶⁰, —C(O)OR⁶⁰, —C(O)NR⁶⁰R⁶¹, —C(O)O⁻, mostpreferably, -M, —R⁶⁰, ═O, —OR⁶⁰, —SR⁶⁰, —NR⁶⁰R⁶¹, —CF₃, —CN, —NO₂,—S(O)₂R⁶⁰, —OP(O)(OR⁶⁰)(OR⁶¹), —C(O)R⁶⁰, —C(O)OR⁶⁰, —C(O)O⁻, where R⁶⁰,R⁶¹ and R⁶² are as defined above.

“Transported by the PEPT1 transporter” refers to the translocation of amolecule across a membrane of a cell expressing the PEPT1 transporter.The translocation occurs through interaction with the transporter and isenergized by cotransport of H⁺ ions across the membrane.

“Treating” or “treatment” of any disease or disorder refers to one ormore of the following: (1) ameliorating the disease or disorder (i.e.,arresting or reducing the development of the disease or at least one ofthe clinical symptoms thereof); (2) ameliorating at least one physicalparameter, which may not be discernible by the patient; (3) inhibitingthe disease or disorder, either physically, (e.g., stabilization of adiscernible symptom), physiologically, (e.g., stabilization of aphysical parameter), or both; and (4) delaying the onset of the diseaseor disorder.

“Therapeutically effective amount” means the amount of a compound orcomposition that, when administered to a patient, is sufficient toeffect the desired therapy. The “therapeutically effective amount” willvary depending on the compound, the disease and its severity and theage, weight, etc., of the patient to be treated.

Reference will now be made in detail to certain preferred compounds andmethods of making and administering these compounds. The invention isnot limited to those preferred compounds and methods but rather isdefined by the claim(s) issuing herefrom.

4.2 Compounds

The compounds disclosed herein are prodrugs of propofol. A first classof propofol prodrugs include compounds of structural Formula (I):

or a pharmaceutically acceptable salt, hydrate, solvate or N-oxidethereof, wherein:

X is selected from the group consisting of a bond, —CH₂—, —NR¹¹—, —O—and —S—;

m is 1 or 2;

n is 0 or 1;

R¹ is selected from the group consisting of hydrogen,[R⁵NH(CHR⁴)_(p)C(O)]—, R⁶—, R⁶C(O)— and R⁶C(O)—;

R² is —OR⁷ or —[NR⁸(CHR⁹)_(q)C(O)OR⁷];

p and q are independently 1 or 2;

R³ is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkoxycarbonyl, aryl, substituted aryl, arylalkyl, carbamoyl,substituted carbamoyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, heteroaryl, substituted heteroaryl andheteroarylalkyl;

each R⁴ is independently selected from the group consisting of hydrogen,alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, substitutedacyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substitutedaryl, arylalkyl, substituted arylalkyl, carbamoyl, substitutedcarbamoyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl and substitutedheteroarylalkyl, or optionally, when R⁴ and R⁵ are attached to adjacentatoms then R⁴ and R⁵ together with the atoms to which they are bondedform a cycloheteroalkyl or substituted cycloheteroalkyl ring;

R⁵ is selected from the group consisting of hydrogen, R⁶—, R⁶C(O)— andR⁶OC(O)—;

R⁶ is selected from the group consisting of alkyl, substituted alkyl,aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, heteroaryl, substitutedheteroaryl and heteroarylalkyl;

R⁷ is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl,cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, heteroaryl,substituted heteroaryl and heteroarylalkyl;

R⁸ is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, aryl, substituted aryl, arylalkyl, cycloalkyl, substitutedcycloalkyl, cycloheteroalkyl, heteroaryl, substituted heteroaryl andheteroarylalkyl;

each R⁹ is independently selected from the group consisting of hydrogen,alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, substitutedacyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substitutedaryl, arylalkyl, substituted arylalkyl, carbamoyl, substitutedcarbamoyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl and substitutedheteroarylalkyl, or optionally, when R⁸ and R⁹ are attached to adjacentatoms then R⁸ and R⁹ together with the atoms to which they are bondedform a cycloheteroalkyl or substituted cycloheteroalkyl ring;

R¹¹ is selected from the group consisting of hydrogen, alkyl,substituted alkyl, aryl, substituted aryl, arylalkyl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, heteroaryl, substitutedheteroaryl and heteroarylalkyl;

with the provisos that:

when R¹ is [R⁵NH(CHR⁴)_(p)C(O)]— then R² is —OR⁷;

and when R² is —[NR⁸(CHR⁹)_(q)C(O)OR⁷] then R¹ is not[R⁵NH(CHR⁴)_(p)C(O)]—.

In one embodiment, a compound of Formula (I) is derived from α-aminoacids (e.g., [H₂N(CHR⁴)C(O)OH] and/or [HNR⁸(CHR⁹)C(O)OH]) including, butnot limited to, the 20 genetically encoded amino acids and the non-codedamino acids such as, for Example, 2,3-diaminobutyric acid,2,4-diaminobutyric acid, hydroxylysine, homoserine, homoarginine,homotyrosine, homocysteine, homophenylalanine, citrulline, sarcosine,orthinine, N-methylleucine, kynurenine, penicillamine,4-aminophenylalanine, 3-(2-naphthyl)alanine, 3-(1-naphthyl)alanine,methionine sulfone, methionine sulfoxide, t-butylalanine,4-hydroxyphenylglycine, aminoalanine, 1,2,3,4tetrahydorisoquinoline-3-carboxylic acid, vinylalanine,propargylglycine, 1,2,4-triazolo-3-alanine, 4,4,4-trifluoro-threonine,thyronine, 6-hydroxytryptophan, 5-hydroxytryptophan,3-hydroxykynurenine, 3-aminotyrosine, trifluoromethylalanine(2-(4-pyridyl)ethyl)cysteine, 3,4-dimethoxy-phenylalanine,3-(2-thiazolyl)alanine, ibotenic acid, quisqualic acid,3-trifluoromethylphenylalanine, 4-trifluoromethylphenylalanine,t-butylglycine, cyclopentylglycine, cyclohexylglycine, phenylglycine,cyclohexylalanine, thiohistidine, 3-methoxytyrosine, norleucine,norvaline, alloisoleucine, thioproline, dehydroproline, hydroxyproline,isonipectotic acid, homoproline, N-acetyl lysine, aminophenylbutyricacid, phenylalanines substituted at the ortho, meta or para position ofthe phenyl moiety with one or two of the following: a (C₁₋₄) alkyl, a(C₁₋₄) alkoxy, halogen or nitro groups or substituted with amethylenedioxy group, β-2- and 3-thienylalanine, β-2- and3-furanylalanine, 2-, 3- and 4-pyridylalanine, β-(benzothienyl-2- and3-yl)alanine, β-(1- and 2-naphthyl)alanine, O-sulfate, O-phosphate andO-carboxylate esters of tyrosine, 3-sulfo-tyrosine, 3-carboxy-tyrosine,3-phospho-tyrosine, 4-methane sulfonic acid ester of tyrosine, 4-methanephosphonic acid ester of tyrosine, 3,5-diiodotyrosine or3-nitrotyrosine.

In one embodiment of a compound of Formula (I), n is 1 and R³ ishydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl,cycloalkyl or heteroaryl. Preferably, R³ is hydrogen, alkyl orsubstituted alkyl, more preferably, R³ is hydrogen or C₁₋₄ alkyl, evenmore preferably, R³ is hydrogen or methyl.

In another embodiment of a compound of Formula (I), n is 1 and R³ ishydrogen, aryl or substituted aryl. Preferably, R³ is hydrogen, phenylor substituted phenyl.

In still another embodiment of a compound of Formula (I), n is 1 and R³is hydrogen, arylalkyl or substituted arylalkyl. Preferably, R³ ishydrogen, benzyl or substituted benzyl.

In still another embodiment of a compound of Formula (I), R¹ is hydrogenor [R⁵NH(CHR⁴)_(p)C(O)]—, where p is 1. Preferably, R⁴ is hydrogen,alkanyl, substituted alkanyl, aryl, substituted aryl, arylalkanyl,substituted arylalkanyl, cycloalkanyl, heteroarylalkanyl or substitutedheteroarylalkanyl, or optionally, R⁴ and R⁵ together with the atoms towhich they are bonded form a cycloheteroalkyl or substitutedcycloheteroalkyl ring.

In still another embodiment of a compound of Formula (I), R¹ is[R⁵NH(CHR⁴)_(n)C(O)]—, p is 1, R⁵ is hydrogen and R⁴ is hydrogen,alkanyl or cycloalkanyl. Preferably, R⁴ is hydrogen, methyl, isopropyl,isobutyl, sec-butyl, t-butyl, cyclopentyl or cyclohexyl.

In still another embodiment of a compound of Formula (I), R¹ is[R⁵NH(CHR⁴)_(p)C(O)]—, p is 1, R⁵ is hydrogen, and R⁴ is substitutedalkanyl. Preferably, R⁴ is —CH₂OH, —CH(OH)CH₃, —CH₂CO₂H, —CH₂CH₂CO₂H,—CH₂CONH₂, —CH₂CH₂CONH₂, —CH₂CH₂SCH₃, —CH₂SH, —CH₂(CH₂)₃NH₂ or—CH₂CH₂CH₂NHC(NH)NH₂.

In still another embodiment of a compound of Formula (I), R¹ is[R⁵NH(CHR⁴)_(p)C(O)]—, p is 1, R⁵ is hydrogen, and R⁴ is aryl,arylalkanyl, substituted arylalkanyl or heteroarylalkanyl. Preferably,R⁴ is phenyl, benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl or3-indolylmethyl.

In still another embodiment of a compound of Formula (I), R¹ is[R⁵NH(CHR⁴)_(p)C(O)]—, p is 1 and R⁴ and R⁵ together with the atoms towhich they are bonded form a cycloheteroalkyl or substitutedcycloheteroalkyl ring. Preferably R⁴ and R⁵ together with the atoms towhich they are bonded form an azetidine, pyrrolidine or piperidine ring.

In still another embodiment of a compound of Formula (I), R¹ is[R⁵NH(CHR⁴)_(p)C(O)]—, p is 1, R⁴ is hydrogen, alkanyl, substitutedalkanyl, aryl, substituted aryl, arylalkanyl, substituted arylalkanyl,cycloalkanyl, heteroarylalkanyl or substituted heteroarylalkanyl, R⁵ isR⁶—, R⁶C(O)— or R⁶OC(O)— and R⁶ is alkyl, substituted alkyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, heteroaryl, substitutedheteroaryl or heteroarylalkyl. Preferably, R⁶ is C₁₋₄ alkyl, phenyl,substituted phenyl, benzyl or substituted benzyl.

In still another embodiment of a compound of Formula (I), R¹ is hydrogenor [R⁵NH(CHR⁴)_(p)C(O)]—, where p is 2. Preferably, R⁴ is hydrogen,alkanyl, substituted alkanyl, aryl, substituted aryl, arylalkanyl,substituted arylalkanyl, cycloalkanyl, heteroarylalkanyl or substitutedheteroarylalkanyl, or optionally, when R⁴ and R⁵ are attached toadjacent atoms then R⁴ and R⁵ together with the atoms to which they arebonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring.

In still another embodiment of a compound of Formula (I), R¹ is[R⁵NH(CHR⁴)_(p)C(O)]—, p is 2 and R⁴ is hydrogen, alkanyl, substitutedalkanyl, aryl, substituted aryl, arylalkanyl, substituted arylalkanyl,cycloalkanyl, heteroarylalkanyl or substituted heteroarylalkanyl.Preferably, R⁴ is hydrogen, C₁₋₄ alkyl, cyclopentyl, cyclohexyl, phenyl,substituted phenyl, benzyl or substituted benzyl.

In still another embodiment of a compound of Formula (I), R¹ is[R⁵NH(CHR⁴)_(p)C(O)]—, p is 2, R⁵ is hydrogen and R⁴ is hydrogen, C₁₋₄alkyl, cyclopentyl, cyclohexyl, phenyl, substituted phenyl, benzyl orsubstituted benzyl.

In still another embodiment of a compound of Formula (I), R² is —OR⁷ andR⁷ is hydrogen, alkyl, aryl, substituted aryl, arylalkyl or substitutedarylalkyl. Preferably, R⁷ is hydrogen, C¹⁴ alkyl, phenyl, substitutedphenyl, benzyl or substituted benzyl.

In still another embodiment of a compound of Formula (I), R² is—[NR⁸(CHR⁹)_(q)C(O)OR⁷], q is 1, R⁷ is hydrogen, alkyl, aryl,substituted aryl, arylalkyl or substituted arylalkyl. Preferably, R⁷ ishydrogen, C₁₋₄ alkyl, phenyl, substituted phenyl, benzyl or substitutedbenzyl.

In still another embodiment of a compound of Formula (I), R² is—[NR⁸(CHR⁹)_(q)C(O)OR⁷], q is 1, R⁸ is hydrogen and R⁹ is hydrogen,alkanyl, substituted alkanyl, aryl, substituted aryl, arylalkanyl,substituted arylalkanyl, cycloalkanyl, heteroarylalkanyl or substitutedheteroarylalkanyl. Preferably, R⁷ hydrogen, alkyl, aryl, substitutedaryl, arylalkyl or substituted arylalkyl, more preferably, R⁷ ishydrogen, C₁₋₄ alkyl, phenyl, substituted phenyl, benzyl or substitutedbenzyl.

In still another embodiment of a compound of Formula (I), R² is—[NR⁸(CHR⁹)_(q)C(O)OR⁷], q is 1, R⁷ is hydrogen, alkyl, aryl,substituted aryl, arylalkyl or substituted arylalkyl, R⁸ is hydrogen andR⁹ is hydrogen, alkanyl or cycloalkanyl. Preferably, R⁹ is hydrogen,methyl, isopropyl, isobutyl, sec-butyl, t-butyl, cyclopentyl orcyclohexyl. Preferably, R⁷ is hydrogen, C₁₋₄ alkyl, phenyl, substitutedphenyl, benzyl or substituted benzyl.

In still another embodiment of a compound of Formula (I), R² is—[NR⁸(CHR⁹)_(q)C(O)OR⁷], q is 1, R⁷ is hydrogen, alkyl, aryl,substituted aryl, arylalkyl or substituted arylalkyl, R⁸ is hydrogen andR⁹ is substituted alkanyl. Preferably, R⁹ is —CH₂OH, —CH(OH)CH₃,—CH₂CO₂H, —CH₂CH₂CO₂H, —CH₂CONH₂, —CH₂CH₂CONH₂, —CH₂CH₂SCH₃, —CH₂SH,—CH₂(CH₂)₃NH₂ or —CH₂CH₂CH₂NHC(NH)NH₂. Preferably, R⁷ is hydrogen, C₁₋₄alkyl, phenyl, substituted phenyl, benzyl or substituted benzyl.

In still another embodiment of a compound of Formula (I), R² is—[NR⁸(CHR⁹)_(q)C(O)OR⁷], q is 1, R⁷ is hydrogen, alkyl, aryl,substituted aryl, arylalkyl or substituted arylalkyl, R⁸ is hydrogen andR⁹ is aryl, arylalkanyl, substituted arylalkanyl or heteroarylalkanyl.Preferably, R⁹ is phenyl, benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl or3-indolylmethyl. Preferably R⁷ is hydrogen, C₁₋₄ alkyl, phenyl,substituted phenyl, benzyl or substituted benzyl.

In still another embodiment of a compound of Formula (I), R² is—[NR⁸(CHR⁹)_(q)C(O)OR⁷], q is 1, R⁷ is hydrogen, alkyl, aryl,substituted aryl, arylalkyl or substituted arylalkyl and R⁸ and R⁹together with the atoms to which they are bonded form a cycloheteroalkylor substituted cycloheteroalkyl ring. Preferably R⁸ and R⁹ together withthe atoms to which they are bonded form an azetidine, pyrrolidine orpiperidine ring. Preferably, R⁷ is hydrogen, C₁₋₄ alkyl, phenyl,substituted phenyl, benzyl or substituted benzyl.

In still another embodiment of a compound of Formula (1), R² is—[NR⁸(CHR⁹)_(q)C(O)OR⁷], q is 2, R⁷ is hydrogen, alkyl, aryl,substituted aryl, arylalkyl or substituted arylalkyl and R⁹ is hydrogen,alkanyl, substituted alkanyl, aryl, substituted aryl, arylalkanyl,substituted arylalkanyl, cycloalkanyl, heteroarylalkanyl or substitutedheteroarylalkanyl. Preferably, R⁷ is hydrogen, C₁₋₄ alkyl, phenyl,substituted phenyl, benzyl or substituted benzyl. Preferably, R⁸ ishydrogen and R⁹ is hydrogen, C₁₋₄ alkyl, cyclopentyl, cyclohexyl,phenyl, substituted phenyl, benzyl or substituted benzyl.

In still another embodiment of a compound of Formula (I), m is 1, n is0, X is a bond, R¹ is [R⁵NH(CHR⁴)_(p)C(O)]—, p is 1, R⁵ is hydrogen, R²is —OR⁷, R⁴ is hydrogen, alkanyl, substituted alkanyl, aryl, substitutedaryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl,heteroarylalkanyl or substituted heteroarylalkanyl and R⁷ is hydrogen,alkyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl.Preferably, R⁷ is hydrogen, C₁₋₄ alkyl, phenyl, substituted phenyl,benzyl or substituted benzyl, more preferably, R⁷ is hydrogen.

In still another embodiment of a compound of Formula (I), m is 1, n is0, X is a bond, R¹ is [R⁵NH(CHR⁴)_(p)C(O)]—, p is 1, R⁵ is hydrogen andR² is —OH to provide a compound of Formula (III):

where R⁴ is hydrogen, alkanyl, substituted alkanyl, aryl, substitutedaryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl,heteroarylalkanyl or substituted heteroarylalkanyl.

In one embodiment of a compound of Formula (III), R⁴ is hydrogen,alkanyl, or cycloalkanyl. Preferably, R⁴ is hydrogen, methyl, isopropyl,isobutyl, sec-butyl, t-butyl, cyclopentyl or cyclohexyl.

In another embodiment of a compound of Formula (III), R⁴ is substitutedalkanyl. Preferably, R⁴ is —CH₂OH, —CH(OH)CH₃, —CH₂CO₂H, —CH₂CH₂CO₂H,—CH₂CONH₂, —CH₂CH₂CONH₂, —CH₂CH₂SCH₃, —CH₂SH, —CH₂(CH₂)₃NH₂ or—CH₂CH₂CH₂NHC(NH)NH₂.

In still another embodiment of a compound of Formula (III), R⁴ is aryl,arylalkanyl, substituted arylalkanyl or heteroarylalkanyl. Preferably,R⁴ is phenyl, benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl or3-indolylmethyl.

In still another embodiment of a compound of Formula (III), the α-carbonof the N-terminal amino acid residue is of the L-configuration. In stillanother embodiment of a compound of Formula (III), the α-carbon of theN-terminal amino acid residue is of the D-configuration. In stillanother embodiment of a compound of Formula (III), the α-carbon of theC-terminal amino acid residue is of the L-configuration. In stillanother embodiment of a compound of Formula (III), the α-carbon of theC-terminal amino acid residue is of the D-configuration. In stillanother embodiment of a compound of Formula (III), the α-carbons of boththe N- and C-terminal amino acid residues are of the L-configuration.

In still another embodiment of a compound of Formula (I), m is 2, n is0, X is a bond, R¹ is [R⁵NH(CHR⁴)_(p)C(O)]—, p is 1, R⁵ is hydrogen, R²is —OR⁷, R⁴ is hydrogen, alkanyl, substituted alkanyl, aryl, substitutedaryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl,heteroarylalkanyl or substituted heteroarylalkanyl and R⁷ is hydrogen,alkyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl.Preferably, R⁷ is hydrogen, C₁₋₄ alkyl, phenyl, substituted phenyl,benzyl or substituted benzyl, more preferably, R⁷ is hydrogen.

In still another embodiment of a compound of Formula (I), m is 2, n is0, X is a bond, R¹ is [R⁵NH(CHR⁴)_(p)C(O)]—, p is 1, R⁵ is hydrogen andR² is —OH to provide a compound of Formula (IV):

where R⁴ is hydrogen, alkanyl, substituted alkanyl, aryl, substitutedaryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl,heteroarylalkanyl or substituted heteroarylalkanyl.

In one embodiment of a compound of Formula (IV), R⁴ is hydrogen, alkanylor cycloalkanyl. Preferably, R⁴ is hydrogen, methyl, isopropyl,isobutyl, sec-butyl, t-butyl, cyclopentyl or cyclohexyl.

In another embodiment of a compound of Formula (IV), R⁴ is substitutedalkanyl. Preferably, R⁴ is —CH₂OH, —CH(OH)CH₃, —CH₂CO₂H, —CH₂CH₂CO₂H,—CH₂CONH₂, —CH₂CH₂CONH₂, —CH₂CH₂SCH₃, —CH₂SH, —CH₂(CH₂)₃NH₂ or—CH₂CH₂CH₂NHC(NH)NH₂.

In still another embodiment of a compound of Formula (IV), R⁴ is aryl,arylalkanyl, substituted arylalkanyl or heteroarylalkanyl. Preferably,R⁴ is phenyl, benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl or3-indolylmethyl.

In still another embodiment of a compound of Formula (IV), the α-carbonof the N-terminal amino acid residue is of the L-configuration. In stillanother embodiment of a compound of Formula (IV), the α-carbon of theN-terminal amino acid residue is of the D-configuration. In stillanother embodiment of a compound of Formula (IV), the α-carbon of theC-terminal amino acid residue is of the L-configuration. In stillanother embodiment of a compound of Formula (IV), the α-carbon of theC-terminal amino acid residue is of the D-configuration. In stillanother embodiment of a compound of Formula (IV), the α-carbons of boththe N- and C-terminal amino acid residues are of the L-configuration.

In still another embodiment of a compound of Formula (I), m is 1, n is0, X is —O—, R¹ is [R⁵NH(CHR⁴)_(p)C(O)]—, p is 1, R⁵ is hydrogen, R² is—OR⁷, R⁴ is hydrogen alkanyl, substituted alkanyl, aryl, substitutedaryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl,heteroarylalkanyl or substituted heteroarylalkanyl and R⁷ is hydrogen,alkyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl.Preferably, R⁷ is hydrogen, C₁₋₄ alkyl, phenyl, substituted phenyl,benzyl or substituted benzyl, more preferably, R⁷ is hydrogen.

In still another embodiment of a compound of Formula (I), m is 1, n is0, X is —O—, R¹ is [R⁵NH(CHR⁴)_(p)C(O)]—, p is 1, R⁵ is hydrogen and R²is —OH to provide a compound of Formula (V):

where R⁴ is hydrogen, alkanyl, substituted alkanyl, aryl, substitutedaryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl,heteroarylalkanyl or substituted heteroarylalkanyl.

In one embodiment of a compound of Formula (V), R⁴ is hydrogen, alkanylor cycloalkanyl. Preferably, R⁴ is hydrogen, methyl, isopropyl,isobutyl, sec-butyl, t-butyl, cyclopentyl or cyclohexyl.

In another embodiment of a compound of Formula (V), R⁴ is substitutedalkanyl. Preferably, R⁴ is —CH₂OH, —CH(OH)CH₃, —CH₂CO₂H, —CH₂CH₂CO₂H,—CH₂CONH₂, —CH₂CH₂CONH₂, —CH₂CH₂SCH₃, —CH₂SH, —CH₂(CH₂)₃NH₂ or—CH₂CH₂CH₂NHC(NH)NH₂.

In still another embodiment of a compound of Formula (V), R⁴ is aryl,arylalkanyl, substituted arylalkanyl or heteroarylalkanyl. Preferably,R⁴ is phenyl, benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl or3-indolylmethyl.

In still another embodiment of a compound of Formula (V), the α-carbonof the N-terminal amino acid residue is of the L-configuration. In stillanother embodiment of a compound of Formula (V), the α-carbon of theN-terminal amino acid residue is of the D-configuration. In stillanother embodiment of a compound of Formula (V), the α-carbon of theC-terminal amino acid residue is of the L-configuration. In stillanother embodiment of a compound of Formula (V), the α-carbon of theC-terminal amino acid residue is of the D-configuration. In stillanother embodiment of a compound of Formula (V), the α-carbons of boththe N- and C-terminal amino acid residues are of the L-configuration.

In still another embodiment of a compound of Formula (I), m is 1, n is0, X is —S—, R¹ is [R⁵NH(CHR⁴)_(p)C(O)]—, p is 1, R⁵ is hydrogen, R² is—OR⁷, R⁴ is hydrogen alkanyl, substituted alkanyl, aryl, substitutedaryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl,heteroarylalkanyl or substituted heteroarylalkanyl and R⁷ is hydrogen,alkyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl.Preferably, R⁷ is hydrogen, C₁₋₄ alkyl, phenyl, substituted phenyl,benzyl or substituted benzyl, more preferably, R⁷ is hydrogen.

In still another embodiment of a compound of Formula (I), m is 1, n is0, X is —S—, R¹ is [R⁵NH(CHR⁴)_(p)C(O)]—, p is 1, R⁵ is hydrogen and R²is —OH to provide a compound of Formula (VI):

where R⁴ is hydrogen, alkanyl, substituted alkanyl, aryl, substitutedaryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl,heteroarylalkanyl or substituted heteroarylalkanyl.

In one embodiment of a compound of Formula (VI), R⁴ is hydrogen,alkanyl, or cycloalkanyl. Preferably, R⁴ is hydrogen, methyl, isopropyl,isobutyl, sec-butyl, t-butyl, cyclopentyl or cyclohexyl.

In another embodiment of a compound of Formula (VI), R⁴ is substitutedalkanyl. Preferably, R⁴ is —CH₂OH, —CH(OH)CH₃, —CH₂CO₂H, —CH₂CH₂CO₂H,—CH₂CONH₂, —CH₂CH₂CONH₂, —CH₂CH₂SCH₃, —CH₂SH, —CH₂(CH₂)₃NH₂ or—CH₂CH₂CH₂NHC(NH)NH₂.

In still another embodiment of a compound of Formula (VI), R⁴ is aryl,arylalkanyl, substituted arylalkanyl or heteroarylalkanyl. Preferably,R⁴ is phenyl, benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl or3-indolylmethyl.

In still another embodiment of a compound of Formula (VI), the α-carbonof the N-terminal amino acid residue is of the L-configuration. In stillanother embodiment of a compound of Formula (VI), the α-carbon of theN-terminal amino acid residue is of the D-configuration. In stillanother embodiment of a compound of Formula (VI), the α-carbon of theC-terminal amino acid residue is of the L-configuration. In stillanother embodiment of a compound of Formula (VI), the α-carbon of theC-terminal amino acid residue is of the D-configuration. In stillanother embodiment of a compound of Formula (VI), the α-carbons of boththe N- and C-terminal amino acid residues are of the L-configuration.

In still another embodiment of a compound of Formula (I), m is 1, n is1, X is a bond, R¹ is [R⁵NH(CHR⁴)_(p)C(O)]—, p is 1, R⁵ is hydrogen, R²is —OR⁷, R³ is hydrogen, alkyl, substituted alkyl, aryl, substitutedaryl, arylalkyl, cycloalkyl or heteroaryl, R⁴ is hydrogen, alkanyl,substituted alkanyl, aryl, substituted aryl, arylalkanyl, substitutedarylalkanyl, cycloalkanyl, heteroarylalkanyl or substitutedheteroarylalkanyl and R⁷ is hydrogen, alkyl, aryl, substituted aryl,arylalkyl or substituted arylalkyl. Preferably, R³ is hydrogen, C₁₋₄alkyl, phenyl, substituted phenyl, benzyl or substituted benzyl. Morepreferably, R³ is hydrogen or methyl. Preferably, R⁷ is hydrogen, C₁₋₄alkyl, phenyl, substituted phenyl, benzyl or substituted benzyl, morepreferably, R⁷ is hydrogen.

In still another embodiment of a compound of Formula (I), m is 1, n is1, X is a bond, R¹ is [R⁵NH(CHR⁴)_(p)C(O)]—, p is 1, R⁵ is hydrogen andR² is —OH to provide a compound of Formula (VII):

where R³ is hydrogen or methyl and R⁴ is hydrogen, alkanyl, substitutedalkanyl, aryl, substituted aryl, arylalkanyl, substituted arylalkanyl,cycloalkanyl, heteroarylalkanyl or substituted heteroarylalkanyl.

In one embodiment of a compound of Formula (VII), R⁴ is hydrogen,alkanyl, or cycloalkanyl. Preferably, R⁴ is hydrogen, methyl, isopropyl,isobutyl, sec-butyl, t-butyl, cyclopentyl or cyclohexyl.

In another embodiment of a compound of Formula (VII), R⁴ is substitutedalkanyl. Preferably, R⁴ is —CH₂OH, —CH(OH)CH₃, —CH₂CO₂H, —CH₂CH₂CO₂H,—CH₂CONH₂, —CH₂CH₂CONH₂, —CH₂CH₂SCH₃, —CH₂SH, —CH₂(CH₂)₃NH₂ or—CH₂CH₂CH₂NHC(NH)NH₂.

In still another embodiment of a compound of Formula (VII), R⁴ is aryl,arylalkanyl, substituted arylalkanyl or heteroarylalkanyl. Preferably,R⁴ is phenyl, benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl or3-indolylmethyl.

In still another embodiment of a compound of Formula (VII), the α-carbonof the N-terminal amino acid residue is of the L-configuration. In stillanother embodiment of a compound of Formula (VII), the α-carbon of theN-terminal amino acid residue is of the D-configuration. In stillanother embodiment of a compound of Formula (VII), the α-carbon of theC-terminal amino acid residue is of the L-configuration. In stillanother embodiment of a compound of Formula (VII), the α-carbon of theC-terminal amino acid residue is of the D-configuration. In stillanother embodiment of a compound of Formula (VII), the α-carbons of boththe N- and C-terminal amino acid residues are of the L-configuration. Instill another embodiment of a compound of Formula (VII), R³ is hydrogen.

In still another embodiment of a compound of Formula (I), m is 2, n is1, X is a bond, R¹ is [R⁵NH(CHR⁴)_(p)C(O)]—, p is 1, R⁵ is hydrogen, R²is —OR⁷, R³ is hydrogen, alkyl, substituted alkyl, aryl, substitutedaryl, arylalkyl, cycloalkyl or heteroaryl, R⁴ is hydrogen, alkanyl,substituted alkanyl, aryl, substituted aryl, arylalkanyl, substitutedarylalkanyl, cycloalkanyl, heteroarylalkanyl or substitutedheteroarylalkanyl and R⁷ is hydrogen, alkyl, aryl, substituted aryl,arylalkyl or substituted arylalkyl. Preferably, R³ is hydrogen, C₁₋₄alkyl, phenyl, substituted phenyl, benzyl or substituted benzyl, morepreferably, R³ is hydrogen or methyl. Preferably, R⁷ is hydrogen, C₁₋₄alkyl, phenyl, substituted phenyl, benzyl or substituted benzyl, morepreferably, R⁷ is hydrogen.

In still another embodiment of a compound of Formula (I), m is 2, n is1, X is a bond, R¹ is [R⁵NH(CHR⁴)_(p)C(O)]—, p is 1, R⁵ is hydrogen andR² is —OH to provide a compound of Formula (VIII):

where R³ is hydrogen or methyl and R⁴ is hydrogen, alkanyl, substitutedalkanyl, aryl, substituted aryl, arylalkanyl, substituted arylalkanyl,cycloalkanyl, heteroarylalkanyl or substituted heteroarylalkanyl.

In one embodiment of a compound of Formula (VIII), R⁴ is hydrogen,alkanyl or cycloalkanyl. Preferably, R⁴ is hydrogen, methyl, isopropyl,isobutyl, sec-butyl, t-butyl, cyclopentyl or cyclohexyl.

In another embodiment of a compound of Formula (VIII), R⁴ is substitutedalkanyl. Preferably, R⁴ is —CH₂OH, —CH(OH)CH₃, —CH₂CO₂H, —CH₂CH₂CO₂H,—CH₂CONH₂, —CH₂CH₂CONH₂, —CH₂CH₂SCH₃, —CH₂SH, —CH₂(CH₂)₃NH₂ or—CH₂CH₂CH₂NHC(NH)NH₂.

In still another embodiment of a compound of Formula (VIII), R⁴ is aryl,arylalkanyl, substituted arylalkanyl or heteroarylalkanyl. Preferably,R⁴ is phenyl, benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl or3-indolylmethyl.

In still another embodiment of a compound of Formula (VIII), theα-carbon of the N-terminal amino acid residue is of the L-configuration.In still another embodiment of a compound of Formula (VIII), theα-carbon of the N-terminal amino acid residue is of the D-configuration.In still another embodiment of a compound of Formula (VIII), theα-carbon of the C-terminal amino acid residue is of the L-configuration.In still another embodiment of a compound of Formula (VIII), theα-carbon of the C-terminal amino acid residue is of the D-configuration.In still another embodiment of a compound of Formula (VIII), theα-carbons of both the N- and C-terminal amino acid residues are of theL-configuration. In still another embodiment of a compound of Formula(VIII), R³ is hydrogen. In still another embodiment of a compound ofFormula (VIII), R³ is hydrogen.

In still another embodiment of a compound of Formula (I), m is 1, n is0, X is a bond, R¹ is selected from the group consisting of hydrogen,R⁶—, R⁶C(O)— and R⁶OC(O)—, R² is —[NR⁸(CHR⁹)_(q)C(O)OR⁷], q is 1, R⁶ isalkyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl, R⁷ isalkyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl, R⁸ ishydrogen or alkyl, R⁹ is hydrogen, alkanyl, substituted alkanyl, aryl,substituted aryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl,heteroarylalkanyl or substituted heteroarylalkanyl, or optionally, R⁸and R⁹ together with the atoms to which they are bonded form acycloheteroalkyl or substituted cycloheteroalkyl ring. Preferably, R¹ ishydrogen. Preferably, R⁶ is C₁₋₄ alkyl, phenyl, substituted phenyl,benzyl or substituted benzyl. Preferably, R⁷ is hydrogen, C₁₋₄ alkyl,phenyl, substituted phenyl, benzyl or substituted benzyl, morepreferably, R⁷ is hydrogen.

In still another embodiment of a compound of Formula (I), m is 1, n is0, X is a bond, R¹ is hydrogen, R² is —[NR⁸(CHR⁹)_(q)C(O)OR⁷], q is 1,R⁷ is hydrogen, alkyl, aryl, substituted aryl, arylalkyl or substitutedarylalkyl, R⁸ is hydrogen or alkyl, R⁹ is hydrogen, alkanyl, substitutedalkanyl, aryl, substituted aryl, arylalkanyl, substituted arylalkanyl,cycloalkanyl, heteroarylalkanyl or substituted heteroarylalkanyl, oroptionally, R⁸ and R⁹ together with the atoms to which they are bondedform a cycloheteroalkyl or substituted cycloheteroalkyl ring.Preferably, R⁷ is hydrogen, C₁₋₄ alkyl, phenyl, substituted phenyl,benzyl or substituted benzyl, more preferably, R⁷ is hydrogen.

In still another embodiment of a compound of Formula (I), m is 1, n is0, X is a bond, R¹ is hydrogen, R² is —[NR⁸(CHR⁹)_(q)C(O)OR⁷], q is 1and R⁷ is hydrogen to provide a compound of Formula (IX):

where R⁸ is hydrogen or methyl and R⁹ is hydrogen, alkanyl, substitutedalkanyl, aryl, substituted aryl, arylalkanyl, substituted arylalkanyl,cycloalkanyl, heteroarylalkanyl or substituted heteroarylalkanyl, oroptionally, R⁸ and R⁹ together with the atoms to which they are bondedform a cycloheteroalkyl or substituted cycloheteroalkyl ring.

In one embodiment of a compound of Formula (IX), R⁹ is hydrogen, alkanylor cycloalkanyl. Preferably, R⁹ is hydrogen, methyl, isopropyl,isobutyl, sec-butyl, t-butyl, cyclopentyl or cyclohexyl.

In another embodiment of a compound of Formula (IX), R⁹ is substitutedalkanyl. Preferably, R⁹ is —CH₂OH, —CH(OH)CH₃, —CH₂CO₂H, —CH₂CH₂CO₂H,—CH₂CONH₂, —CH₂CH₂CONH₂, —CH₂CH₂SCH₃, —CH₂SH, —CH₂(CH₂)₃NH₂ or—CH₂CH₂CH₂NHC(NH)NH₂.

In still another embodiment of a compound of Formula (IX), R⁹ is aryl,arylalkanyl, substituted arylalkanyl or heteroarylalkanyl. Preferably,R⁹ is phenyl, benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl or3-indolylmethyl.

In still another embodiment of a compound of Formula (IX), R⁸ and R⁹together with the atoms to which they are bonded form a cycloheteroalkylor substituted cycloheteroalkyl ring. Preferably, R⁸ and R⁹ togetherwith the atoms to which they are bonded form an azetidine, pyrrolidineor piperidine ring.

In still another embodiment of a compound of Formula (IX), the α-carbonof the N-terminal amino acid residue is of the L-configuration. In stillanother embodiment of a compound of Formula (IX), the α-carbon of theN-terminal amino acid residue is of the D-configuration. In stillanother embodiment of a compound of Formula (IX), the α-carbon of theC-terminal amino acid residue is of the L-configuration. In stillanother embodiment of a compound of Formula (IX), the α-carbon of theC-terminal amino acid residue is of the D-configuration. In stillanother embodiment of a compound of Formula (IX), the α-carbons of boththe N- and C-terminal amino acid residues are of the L-configuration. Instill another embodiment of a compound of Formula (IX), R⁸ is hydrogen.

In still another embodiment of a compound of Formula (I), m is 2, n is0, X is a bond, R¹ is hydrogen, R² is —[NR⁸(CHR⁹)_(q)C(O)OR⁷], q is 1,R⁷ is hydrogen, alkyl, aryl, substituted aryl, arylalkyl or substitutedarylalkyl, R⁸ is hydrogen or alkyl, R⁹ is hydrogen, alkanyl, substitutedalkanyl, aryl, substituted aryl, arylalkanyl, substituted arylalkanyl,cycloalkanyl, heteroarylalkanyl or substituted heteroarylalkanyl oroptionally, R⁸ and R⁹ together with the atoms to which they are bondedform a cycloheteroalkyl or substituted cycloheteroalkyl ring.Preferably, R⁷ is hydrogen, C₁₋₄ alkyl, phenyl, substituted phenyl,benzyl or substituted benzyl, more preferably, R⁷ is hydrogen.

In still another embodiment of a compound of Formula (I), m is 2, n is0, X is a bond, R¹ is hydrogen, R² is —[NR⁸(CHR⁹)_(q)C(O)OR⁷], q is 1and R⁷ is hydrogen to provide a compound of Formula (X):

R⁸ is hydrogen or methyl and R⁹ is hydrogen, alkanyl, substitutedalkanyl, aryl, substituted aryl, arylalkanyl, substituted arylalkanyl,cycloalkanyl, heteroarylalkanyl or substituted heteroarylalkanyl, oroptionally, R⁸ and R⁹ together with the atoms to which they are bondedform a cycloheteroalkyl or substituted cycloheteroalkyl ring.

In one embodiment of a compound of Formula (X), R⁹ is hydrogen, alkanylor cycloalkanyl. Preferably, R⁹ is hydrogen, methyl, isopropyl,isobutyl, sec-butyl, t-butyl, cyclopentyl or cyclohexyl.

In another embodiment of a compound of Formula (X), R⁹ is substitutedalkanyl. Preferably, R⁹ is —CH₂OH, —CH(OH)CH₃, —CH₂CO₂H, —CH₂CH₂CO₂H,—CH₂CONH₂, —CH₂CH₂CONH₂, —CH₂CH₂SCH₃, —CH₂SH, —CH₂(CH₂)₃NH₂ or—CH₂CH₂CH₂NHC(NH)NH₂.

In still another embodiment of a compound of Formula (X), R¹⁹ is aryl,arylalkanyl, substituted arylalkanyl or heteroarylalkanyl. Preferably,R⁹ is phenyl, benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl or3-indolylmethyl.

In still another embodiment of a compound of Formula (X), R⁸ and R⁹together with the atoms to which they are bonded form a cycloheteroalkylor substituted cycloheteroalkyl ring. Preferably, R⁸ and R⁹ togetherwith the atoms to which they are bonded form an azetidine, pyrrolidineor piperidine ring.

In still another embodiment of a compound of Formula (X), the α-carbonof the N-terminal amino acid residue is of the L-configuration. In stillanother embodiment of a compound of Formula (X), the α-carbon of theN-terminal amino acid residue is of the D-configuration. In stillanother embodiment of a compound of Formula (X), the α-carbon of theC-terminal amino acid residue is of the L-configuration. In stillanother embodiment of a compound of Formula (X), the α-carbon of theC-terminal amino acid residue is of the D-configuration. In stillanother embodiment of a compound of Formula (X), the α-carbons of boththe N- and C-terminal amino acid residues are of the L-configuration. Instill another embodiment of a compound of Formula (X), R³ is hydrogen.In still another embodiment of a compound of Formula (X), R⁸ ishydrogen.

In still another embodiment of a compound of Formula (I), m is 1, n is1, X is a bond, R¹ is hydrogen, R² is —[NR⁸(CHR⁹)_(q)C(O)OR⁷], q is 1,R³ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,arylalkyl, cycloalkyl or heteroaryl, R⁷ is hydrogen, alkyl, substitutedalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl,cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, heteroaryl,substituted heteroaryl or heteroarylalkyl, R⁸ is hydrogen or methyl, R⁹is hydrogen, alkanyl, substituted alkanyl, aryl, substituted aryl,arylalkanyl, substituted arylalkanyl, cycloalkanyl, heteroarylalkanyl orsubstituted heteroarylalkanyl, or optionally, R⁸ and R⁹ together withthe atoms to which they are bonded form a cycloheteroalkyl orsubstituted cycloheteroalkyl ring. Preferably, R³ is hydrogen, C₁₋₄alkyl, phenyl, substituted phenyl, benzyl or substituted benzyl. Morepreferably, R³ is hydrogen or methyl. Preferably R⁷ is hydrogen, C₁₋₄alkyl, phenyl, substituted phenyl, benzyl or substituted benzyl. Morepreferably, R⁷ is hydrogen.

In still another embodiment of a compound of Formula (I), m is 1, n is1, X is a bond, R¹ is hydrogen, R² is —[NR⁸(CHR⁹)_(q)C(O)OR⁷], q is 1and R⁷ is hydrogen to provide a compound of Formula (XI):

where R³ is hydrogen or methyl, R⁸ is hydrogen or methyl and R⁹ ishydrogen, alkanyl, substituted alkanyl, aryl, substituted aryl,arylalkanyl, substituted arylalkanyl, cycloalkanyl, heteroarylalkanyl orsubstituted heteroarylalkanyl, or optionally, R⁸ and R⁹ together withthe atoms to which they are bonded, form a cycloheteroalkyl orsubstituted cycloheteroalkyl ring.

In one embodiment of a compound of Formula (XI), R⁹ is hydrogen, alkanylor cycloalkanyl. Preferably, R⁹ is hydrogen, methyl, isopropyl,isobutyl, sec-butyl, t-butyl, cyclopentyl or cyclohexyl.

In another embodiment of a compound of Formula (XI), R⁹ is substitutedalkanyl. Preferably, R⁹ is —CH₂OH, —CH(OH)CH₃, —CH₂CO₂H, —CH₂CH₂CO₂H,—CH₂CONH₂, —CH₂CH₂CONH₂, —CH₂CH₂SCH₃, —CH₂SH, —CH₂(CH₂)₃NH₂ or—CH₂CH₂CH₂NHC(NH)NH₂.

In still another embodiment of a compound of Formula (XI), R⁹ is aryl,arylalkanyl, substituted arylalkanyl or heteroarylalkanyl. Preferably,R⁹ is phenyl, benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl or3-indolylmethyl.

In still another embodiment of a compound of Formula (XI), R⁸ and R⁹together with the atoms to which they are bonded form a cycloheteroalkylor substituted cycloheteroalkyl ring. Preferably, R⁵ and R⁹ togetherwith the atoms to which they are bonded form an azetidine, pyrrolidineor piperidine ring.

In still another embodiment of a compound of Formula (XI), the α-carbonof the N-terminal amino acid residue is of the L-configuration. In stillanother embodiment of a compound of Formula (XI), the α-carbon of theN-terminal amino acid residue is of the D-configuration. In stillanother embodiment of a compound of Formula (XI), the α-carbon of theC-terminal amino acid residue is of the L-configuration. In stillanother embodiment of a compound of Formula (XI), the α-carbon of theC-terminal amino acid residue is of the D-configuration. In stillanother embodiment of a compound of Formula (XI), the α-carbons of boththe N- and C-terminal amino acid residues are of the L-configuration. Instill another embodiment of a compound of Formula (XI), R³ is hydrogen.In still another embodiment of a compound of Formula (XI), R⁸ ishydrogen.

In still another embodiment of a compound of Formula (I), m is 1, n is0, X is a bond, R¹ is hydrogen, R² is —OR⁷ and R⁷ is hydrogen, alkyl,aryl, substituted aryl, arylalkyl or substituted arylalkyl. Preferably,R⁷ is hydrogen, C₁₋₄ alkyl, phenyl, substituted phenyl, benzyl orsubstituted benzyl, more preferably, R⁷ is hydrogen.

In still another embodiment of a compound of Formula (I), m is 1, n is0, X is a bond, R¹ is hydrogen, R² is —OR⁷ and R⁷ is hydrogen to providea compound of Formula (XII):

In one embodiment of a compound of Formula (XII), the α-carbon of theamino acid residue is of the L-configuration. In another embodiment of acompound of Formula (XII), the α-carbon of the amino acid residue is ofthe D-configuration.

In still another embodiment of a compound of Formula (I), m is 2, n is0, X is a bond, R¹ is hydrogen, R² is —OR⁷ and R⁷ is hydrogen, alkyl,aryl, substituted aryl, arylalkyl or substituted arylalkyl. Preferably,R⁷ is hydrogen, C₁₋₄ alkyl, phenyl, substituted phenyl, benzyl orsubstituted benzyl, more preferably, R⁷ is hydrogen.

In still another embodiment of a compound of Formula (I), m is 2, n is0, X is a bond, R¹ is hydrogen, R² is —OR⁷ and R⁷ is hydrogen to providea compound of Formula (XIII):

In one embodiment of a compound of Formula (XIII), the α-carbon of theamino acid residue is of the L-configuration. In another embodiment of acompound of Formula (XIII), the α-carbon of the amino acid residue is ofthe D-configuration.

In still another embodiment of a compound of Formula (I), m is 1, n is1, X is a bond, R¹ is hydrogen, R² is —OR⁷, R³ is hydrogen, alkyl,substituted alkyl, aryl, substituted aryl, arylalkyl, cycloalkyl orheteroaryl and R⁷ is hydrogen, alkyl, aryl, substituted aryl, arylalkylor substituted arylalkyl. Preferably, R³ is hydrogen, C₁₋₄ alkyl,phenyl, substituted phenyl, benzyl or substituted benzyl, morepreferably, R³ is hydrogen or methyl. Preferably, R⁷ is hydrogen, C₁₋₄alkyl, phenyl, substituted phenyl, benzyl or substituted benzyl, morepreferably, R⁷ is hydrogen.

In still another embodiment of a compound of Formula (I), m is 1, n is1, X is a bond, R¹ is hydrogen, R² is —OR⁷ and R⁷ is hydrogen to providea compound of Formula (XIV):

wherein R³ is hydrogen or methyl.

In one embodiment of a compound of Formula (XIV), the α-carbon of theamino acid residue is of the L-configuration. In another embodiment of acompound of Formula (XIV), the α-carbon of the amino acid residue is ofthe D-configuration.

In still another embodiment of a compound of Formula (I), m is 2, n is1, X is a bond, R¹ is hydrogen, R² is —OR⁷, R³ is hydrogen, alkyl,substituted alkyl, aryl, substituted aryl, arylalkyl, cycloalkyl orheteroaryl and R⁷ is hydrogen, alkyl, aryl, substituted aryl, arylalkylor substituted arylalkyl. Preferably, R³ is hydrogen, C₁₋₄ alkyl,phenyl, substituted phenyl, benzyl or substituted benzyl, morepreferably, R³ is hydrogen or methyl. Preferably, R⁷ is hydrogen, C₁₋₄alkyl, phenyl, substituted phenyl, benzyl or substituted benzyl, morepreferably, R⁷ is hydrogen.

In still another embodiment of a compound of Formula (I), m is 2, n is1, X is a bond, R¹ is hydrogen, R² is —OR⁷ and R⁷ is hydrogen to providea compound of Formula (XV):

wherein R³ is hydrogen or methyl.

In one embodiment of a compound of Formula (XIV), the α-carbon of theamino acid residue is of the L-configuration. In another embodiment of acompound of Formula (XIV), the α-carbon of the amino acid residue is ofthe D-configuration.

Another class of propofol prodrugs include compounds of structuralFormula (II):

or a pharmaceutically acceptable salt, hydrate, solvate or N-oxidethereof, wherein:

R¹⁰ is hydrogen or [R⁵NH(CHR⁴)_(p)C(O)]—;

n is 0 or 1;

p and q are independently 1 or 2;

R³ is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkoxycarbonyl, aryl, substituted aryl, arylalkyl, carbamoyl,substituted carbamoyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, heteroaryl, substituted heteroaryl andheteroarylalkyl;

each R⁴ is independently selected from the group consisting of hydrogen,alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, substitutedacyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substitutedaryl, arylalkyl, substituted arylalkyl, carbamoyl, substitutedcarbamoyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl and substitutedheteroarylalkyl, or optionally, when R⁴ and R⁵ are attached to adjacentatoms then R⁴ and R⁵ together with the atoms to which they are bondedform a cycloheteroalkyl or substituted cycloheteroalkyl ring;

R⁵ is selected from the group consisting of hydrogen, R⁶—, R⁶C(O)— andR⁶OC(O)—;

R⁶ is selected from the group consisting of alkyl, substituted alkyl,aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, heteroaryl, substitutedheteroaryl and heteroarylalkyl;

R⁸ is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, aryl, substituted aryl, arylalkyl, cycloalkyl, substitutedcycloalkyl, cycloheteroalkyl, heteroaryl, substituted heteroaryl andheteroarylalkyl;

each R⁹ is independently selected from the group consisting of hydrogen,alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, substitutedacyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substitutedaryl, arylalkyl, substituted arylalkyl, carbamoyl, substitutedcarbamoyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl and substitutedheteroarylalkyl, or optionally, when R⁸ and R⁹ are attached to adjacentatoms then R⁸ and R⁹ together with the atoms to which they are bondedform a cycloheteroalkyl or substituted cycloheteroalkyl ring:

with the proviso that when R¹⁰ is hydrogen then n is 1.

In one embodiment, a compound of Formula (II) is derived from α-aminoacids (e.g., [H₂N(CHR⁴)C(O)OH] and/or [HNR⁸(CHR⁹)C(O)OH]) including, butnot limited to, the 20 genetically encoded amino acids and the non-codedamino acids 2,3-diaminobutyric acid, 2,4-diaminobutyric acid,hydroxylysine, homoserine, homoarginine, homotyrosine, homocysteine,homophenylalanine, citrulline, sarcosine, orthinine, N-methylleucine,kynurenine, penicillamine, 4-aminophenylalanine, 3-(2-naphthyl)alanine,3-(1-naphthyl)alanine, methionine sulfone, methionine sulfoxide,t-butylalanine, 4-hydroxyphenylglycine, aminoalanine, 1,2,3,4tetrahydorisoquinoline-3-carboxylic acid, vinylalanine,propargylglycine, 1,2,4-triazolo-3-alanine, 4,4,4-trifluoro-threonine,thyronine, 6-hydroxytryptophan, 5-hydroxytryptophan,3-hydroxykynurenine, 3-aminotyrosine, trifluoromethylalanine(2-(4-pyridyl)ethyl)cysteine, 3,4-dimethoxy-phenylalanine,3-(2-thiazolyl)alanine, ibotenic acid, quisqualic acid,3-trifluoromethylphenylalanine, 4-trifluoromethylphenylalanine,t-butylglycine, cyclopentylglycine, cyclohexylglycine, phenylglycine,cyclohexylalanine, thiohistidine, 3-methoxytyrosine, norleucine,norvaline, alloisoleucine, thioproline, dehydroproline, hydroxyproline,isonipectotic acid, homoproline, N-acetyl lysine, aminophenylbutyricacid, phenylalanines substituted at the ortho, meta or para position ofthe phenyl moiety with one or two of the following: a (C₁–C₄) alkyl, a(C₁–C₄) alkoxy, halogen or nitro groups or substituted with amethylenedioxy group, β-2- and 3-thienylalanine, β-2- and3-furanylalanine, 2-, 3- and 4-pyridylalanine, β-(benzothienyl-2- and3-yl)alanine, β-(1- and 2-naphthyl)alanine, O-sulfate, O-phosphate andO-carboxylate esters of tyrosine, 3-sulfo-tyrosine, 3-carboxy-tyrosine,3-phospho-tyrosine, 4-methane sulfonic acid ester of tyrosine, 4-methanephosphonic acid ester of tyrosine, 3,5-diiodotyrosine and3-nitrotyrosine.

In one embodiment of a compound of Formula (II), n is 1 and R³ ishydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl,cycloalkyl or heteroaryl. In another embodiment, n is 1 and R³ ishydrogen, alkyl or substituted alkyl. Preferably, R³ is hydrogen or C₁₋₄alkyl.

In still another embodiment of a compound of Formula (II), n is 1 and R³is hydrogen, aryl or substituted aryl. Preferably, R³ is hydrogen,phenyl or substituted phenyl.

In still another embodiment of a compound of Formula (II), n is 1 and R³is hydrogen, arylalkyl or substituted arylalkyl. Preferably, R³ ishydrogen, benzyl or substituted benzyl.

In still another embodiment of a compound of Formula (II), R¹⁰ is[R⁵NH(CHR⁴)_(p)C(O)]—, p is 1 and R⁴ is hydrogen, alkanyl, substitutedalkanyl, aryl, substituted aryl, arylalkanyl, substituted arylalkanyl,cycloalkanyl, heteroarylalkanyl or substituted heteroarylalkanyl, oroptionally, R⁴ and R⁵ together with the atoms to which they are bonded,form a cycloheteroalkyl or substituted cycloheteroalkyl ring.

In still another embodiment of a compound of Formula (II), R¹⁰ is[R⁵NH(CHR⁴)_(n)C(O)]—, p is 1, R⁵ is hydrogen and R⁴ is hydrogen,alkanyl or cycloalkanyl. Preferably, R⁴ is hydrogen, methyl, isopropyl,isobutyl, sec-butyl, t-butyl, cyclopentyl or cyclohexyl.

In still another embodiment of a compound of Formula (II), R¹⁰ is[R⁵NH(CHR⁴)_(p)C(O)]—, p is 1, R⁵ is hydrogen and R⁴ is substitutedalkanyl. Preferably, R⁴ is —CH₂OH, —CH(OH)CH₃, —CH₂CO₂H, —CH₂CH₂CO₂H,—CH₂CONH₂, —CH₂CH₂CONH₂, —CH₂CH₂SCH₃, —CH₂SH, —CH₂(CH₂)₃NH₂ or—CH₂CH₂CH₂NHC(NH)NH₂.

In still another embodiment of a compound of Formula (II), R¹⁰ is[R⁵NH(CHR⁴)_(p)C(O)]—, p is 1, R⁵ is hydrogen and R⁴ is aryl,arylalkanyl, substituted arylalkanyl or heteroarylalkanyl. Preferably,R⁴ is phenyl, benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl or3-indolylmethyl.

In still another embodiment of a compound of Formula (II), R¹⁰ is[R⁵NH(CHR⁴)_(p)C(O)]—, p is 1 and R⁴ and R⁵ together with the atoms towhich they are bonded form a cycloheteroalkyl or substitutedcycloheteroalkyl ring. Preferably, R⁴ and R⁵ together with the atoms towhich they are bonded form an azetidine, pyrrolidine or piperidine ring.

In still another embodiment of a compound of Formula (II), R¹⁰ is[R⁵NH(CHR⁴)_(n)C(O)]—, p is 1, R⁴ is hydrogen, alkanyl, substitutedalkanyl, aryl, substituted aryl, arylalkanyl, substituted arylalkanyl,cycloalkanyl, heteroarylalkyl or substituted heteroarylalkyl, R⁵ is R⁶—,R⁶C(O)— or R⁶OC(O)—, and R⁶ is alkyl, substituted alkyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, heteroaryl, substitutedheteroaryl or heteroarylalkyl. Preferably R⁶ is selected from the groupconsisting of C₁₋₄ alkyl, phenyl, substituted phenyl, benzyl orsubstituted benzyl.

In still another embodiment of a compound of Formula (II), R¹⁰ is[R⁵NH(CHR⁴)_(p)C(O)]—, p is 2 and each R⁴ is independently hydrogen,alkanyl, substituted alkanyl, aryl, substituted aryl, arylalkanyl,substituted arylalkanyl, cycloalkanyl, heteroarylalkanyl or substitutedheteroarylalkanyl. Preferably, each R⁴ is independently hydrogen, C₁₋₄alkyl, cyclopentyl, cyclohexyl, phenyl, substituted phenyl, benzyl orsubstituted benzyl. More preferably, R¹⁰ is [R⁵NH(CHR⁴)_(p)C(O)]—, p is2, R⁵ is hydrogen, and each R⁴ is independently hydrogen, C₁₋₄ alkyl,cyclopentyl, cyclohexyl, phenyl, substituted phenyl, benzyl orsubstituted benzyl.

In still another embodiment of a compound of Formula (II), q is 1, R⁸ ishydrogen or methyl and R⁹ is hydrogen, alkanyl, substituted alkanyl,aryl, substituted aryl, arylalkanyl, substituted arylalkanyl,cycloalkanyl, heteroarylalkanyl or substituted heteroarylalkanyl.

In still another embodiment of a compound of Formula (II), q is 1, R⁸ ishydrogen or methyl and R⁹ is hydrogen, alkanyl or cycloalkanyl.Preferably, R⁹ is hydrogen, methyl, isopropyl, isobutyl, sec-butyl,t-butyl, cyclopentyl or cyclohexyl.

In still another embodiment of a compound of Formula (II), q is 1, R⁸ ishydrogen or methyl and R⁹ is substituted alkanyl. Preferably, R⁹ is—CH₂OH, —CH(OH)CH₃, —CH₂CO₂H, —CH₂CH₂CO₂H, —CH₂CONH₂, —CH₂CH₂CONH₂,—CH₂CH₂SCH₃, —CH₂SH, —CH₂(CH₂)₃NH₂ or —CH₂CH₂CH₂NHC(NH)NH₂.

In still another embodiment of a compound of Formula (II), q is 1, R⁸ ishydrogen or methyl and R⁹ is aryl, arylalkanyl, substituted arylalkanylor heteroarylalkanyl. Preferably, R⁹ is phenyl, benzyl, 4-hydroxybenzyl,4-imidazolylmethyl or 3-indolylmethyl.

In still another embodiment of a compound of Formula (II), q is 1, andR⁸ and R⁹ together with the atoms to which they are bonded form acycloheteroalkyl or substituted cycloheteroalkyl ring. Preferably R⁸ andR⁹ together with the atoms to which they are bonded form an azetidine,pyrrolidine or piperidine ring.

In still another embodiment of a compound of Formula (II), q is 2, R⁸ ishydrogen or methyl and each R⁹ is independently hydrogen, alkanyl,substituted alkanyl, aryl, substituted aryl, arylalkanyl, substitutedarylalkanyl, cycloalkanyl, heteroarylalkanyl or substitutedheteroarylalkanyl. More preferably, R⁸ is hydrogen and each R⁹ isindependently hydrogen, C₁₋₄ alkyl, cyclopentyl, cyclohexyl, phenyl,substituted phenyl, benzyl or substituted benzyl.

In still another embodiment of a compound of Formula (II), n is 0, q is1, R¹⁰ is [R⁵NH(CHR⁴)PC(O)]—, p is 1, and R⁵ is hydrogen to provide acompound of Formula (XVI):

wherein R⁴ is hydrogen, alkanyl, substituted alkanyl, aryl, substitutedaryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl,heteroarylalkanyl or substituted heteroarylalkanyl, R⁸ is hydrogen ormethyl and R⁹ is hydrogen, alkanyl, substituted alkanyl, aryl,substituted aryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl,heteroarylalkanyl or substituted heteroarylalkanyl, or optionally, R⁸and R⁹ together with the atoms to which they are bonded, form acycloheteroalkyl or substituted cycloheteroalkyl ring.

In one embodiment of a compound of Formula (XVI), R⁸ is hydrogen and R⁹is hydrogen, methyl, isopropyl, isobutyl, sec-butyl, t-butyl,cyclopentyl, cyclohexyl, —CH₂OH, —CH(OH)CH₃, —CH₂CO₂H, —CH₂CH₂CO₂H,—CH₂CONH₂, —CH₂CH₂CONH₂, —CH₂CH₂SCH₃, —CH₂SH, —CH₂(CH₂)₃NH₂,—CH₂CH₂CH₂NHC(NH)NH₂, phenyl, benzyl, 4-hydroxybenzyl,4-imidazolylmethyl, 3-indolylmethyl, or optionally, R⁸ and R⁹ togetherwith the atoms to which they are bonded form an azetidine, pyrrolidineor piperidine ring.

In another embodiment of a compound of Formula (XVI), R⁴ is hydrogen,alkanyl or cycloalkanyl. Preferably, R⁴ is hydrogen, methyl, isopropyl,isobutyl, sec-butyl, t-butyl, cyclopentyl or cyclohexyl. Preferably, R⁸is hydrogen and R⁹ is hydrogen, methyl, isopropyl, isobutyl, sec-butyl,t-butyl, cyclopentyl, cyclohexyl, —CH₂OH, —CH(OH)CH₃, —CH₂CO₂H,—CH₂CH₂CO₂H, —CH₂CONH₂, —CH₂CH₂CONH₂, —CH₂CH₂SCH₃, —CH₂SH,—CH₂(CH₂)₃NH₂, —CH₂CH₂CH₂NHC(NH)NH₂, phenyl, benzyl, 4-hydroxybenzyl,4-imidazolylmethyl or 3-indolylmethyl, or optionally, R⁸ and R⁹ togetherwith the atoms to which they are bonded, form an azetidine, pyrrolidineor piperidine ring.

In still another embodiment of a compound of Formula (XVI), R⁴ issubstituted alkanyl. Preferably, R⁴ is —CH₂OH, —CH(OH)CH₃, —CH₂CO₂H,—CH₂CH₂CO₂H, —CH₂CONH₂, —CH₂CH₂CONH₂, —CH₂CH₂SCH₃, —CH₂SH, —CH₂(CH₂)₃NH₂or —CH₂CH₂CH₂NHC(NH)NH₂. Preferably, R⁸ is hydrogen and R⁹ is selectedfrom the group consisting of hydrogen, methyl, isopropyl, isobutyl,sec-butyl, t-butyl, cyclopentyl, cyclohexyl, —CH₂OH, —CH(OH)CH₃,—CH₂CO₂H, —CH₂CH₂CO₂H, —CH₂CONH₂, —CH₂CH₂CONH₂, —CH₂CH₂SCH₃, —CH₂SH,—CH₂(CH₂)₃NH₂, —CH₂CH₂CH₂NHC(NH)NH₂, phenyl, benzyl, 4-hydroxybenzyl,4-imidazolylmethyl or 3-indolylmethyl, or optionally, R⁸ and R⁹ togetherwith the atoms to which they are bonded, form an azetidine, pyrrolidineor piperidine ring.

In still another embodiment of a compound of Formula (XVI), R⁴ is aryl,arylalkanyl, substituted arylalkanyl or heteroarylalkanyl. Preferably,R⁴ is phenyl, benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl or3-indolylmethyl. Preferably, R⁸ is hydrogen and R⁹ is hydrogen, methyl,isopropyl, isobutyl, sec-butyl, t-butyl, cyclopentyl, cyclohexyl,—CH₂OH, —CH(OH)CH₃, —CH₂CO₂H, —CH₂CH₂CO₂H, —CH₂CONH₂, —CH₂CH₂CONH₂,—CH₂CH₂SCH₃, —CH₂SH, —CH₂(CH₂)₃NH₂, —CH₂CH₂CH₂NHC(NH)NH₂, phenyl,benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl or 3-indolylmethyl oroptionally, R⁸ and R⁹ together with the atoms to which they are bonded,form an azetidine, pyrrolidine or piperidine ring.

In still another embodiment of a compound of Formula (XVI), the α-carbonof the N-terminal amino acid residue is of the L-configuration. In stillanother embodiment of a compound of Formula (XVI), the α-carbon of theN-terminal amino acid residue is of the D-configuration. In stillanother embodiment of a compound of Formula (XVI), the α-carbon of theC-terminal amino acid residue is of the L-configuration. In stillanother embodiment of a compound of Formula (XVI), the α-carbon of theC-terminal amino acid residue is of the D-configuration. In stillanother embodiment of a compound of Formula (XVI), the α-carbons of boththe N- and C-terminal amino acid residues are of the L-configuration.

In still another embodiment of a compound of Formula (II), n is 1, q is1, R¹⁰ is hydrogen, R³ is hydrogen, alkyl, substituted alkyl, aryl,substituted aryl, arylalkyl, cycloalkyl or heteroaryl, R⁸ is hydrogen,R⁹ is hydrogen, alkanyl, substituted alkanyl, aryl, substituted aryl,arylalkanyl, substituted arylalkanyl, cycloalkanyl, heteroarylalkanyl orsubstituted heteroarylalkanyl, or optionally, R⁸ and R⁹ together withthe atoms to which they are bonded, form a cycloheteroalkyl orsubstituted cycloheteroalkyl ring. Preferably, R³ is hydrogen, C₁₋₄alkyl, phenyl, substituted phenyl, benzyl or substituted benzyl, morepreferably, R³ is hydrogen or methyl.

In still another embodiment of a compound of Formula (II), n is 1, q is1, and R¹⁰ is hydrogen, to provide a compound of Formula (XVII):

wherein R³ is hydrogen or methyl, R⁸ is hydrogen or methyl and R⁹ ishydrogen, alkanyl, substituted alkanyl, aryl, substituted aryl,arylalkanyl, substituted arylalkanyl, cycloalkanyl, heteroarylalkanyl orsubstituted heteroarylalkanyl, or optionally, R⁸ and R⁹ together withthe atoms to which they are bonded form a cycloheteroalkyl orsubstituted cycloheteroalkyl ring. Preferably, in a compound of Formula(XVII), R⁸ is hydrogen.

In one embodiment of a compound of Formula (XVII), R⁹ is hydrogen,alkanyl or cycloalkanyl. Preferably, R⁹ is hydrogen, methyl, isopropyl,isobutyl, sec-butyl, t-butyl, cyclopentyl or cyclohexyl.

In another embodiment of a compound of Formula (XVII), R⁹ is substitutedalkanyl. Preferably, R⁹ is —CH₂OH, —CH(OH)CH₃, —CH₂CO₂H, —CH₂CH₂CO₂H,—CH₂CONH₂, —CH₂CH₂CONH₂, —CH₂CH₂SCH₃, —CH₂SH, —CH₂(CH₂)₃NH₂ or—CH₂CH₂CH₂NHC(NH)NH₂.

In still another embodiment of a compound of Formula (XVII), R⁹ is aryl,arylalkanyl, substituted arylalkanyl or heteroarylalkanyl. Preferably,R⁹ is phenyl, benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl or3-indolylmethyl.

In still another embodiment of a compound of Formula (XVII), R⁸ and R⁹together with the atoms to which they are bonded form a cycloheteroalkylor substituted cycloheteroalkyl ring. Preferably, R⁸ and R⁹ togetherwith the atoms to which they are bonded form an azetidine, pyrrolidineor piperidine ring.

In one embodiment of a compound of Formula (XVII), the α-carbon of theamino acid residue is of the L-configuration. In another embodiment of acompound of Formula (XVII), the α-carbon of the amino acid residue is ofthe D-configuration.

In still another embodiment of a compound of Formula (XVII), R³ ishydrogen.

In still another embodiment of a compound of Formula (II), n is 1, q is1, R¹⁰ is [R⁵NH(CHR⁴)_(p)C(O)]—, p is 1, R³ is hydrogen, alkyl,substituted alkyl, aryl, substituted aryl, arylalkyl, cycloalkyl orheteroaryl, R⁴ is hydrogen, alkanyl, substituted alkanyl, aryl,substituted aryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl,heteroarylalkanyl or substituted heteroarylalkanyl, R⁵ is hydrogen, R⁸is hydrogen or methyl, R⁹ is hydrogen, alkanyl, substituted alkanyl,aryl, substituted aryl, arylalkanyl, substituted arylalkanyl,cycloalkanyl, heteroarylalkanyl or substituted heteroarylalkanyl, oroptionally, R⁸ and R⁹ together with the atoms to which they are bonded,form a cycloheteroalkyl or substituted cycloheteroalkyl ring. PreferablyR³ is hydrogen, C₁₋₄ alkyl, phenyl, substituted phenyl, benzyl orsubstituted benzyl, more preferably, R³ is hydrogen or methyl.Preferably, R⁸ is hydrogen and R⁹ is hydrogen, methyl, isopropyl,isobutyl, sec-butyl, t-butyl, cyclopentyl, cyclohexyl, —CH₂OH,—CH(OH)CH₃, —CH₂CO₂H, —CH₂CH₂CO₂H, —CH₂CONH₂, —CH₂CH₂CONH₂, —CH₂CH₂SCH₃,—CH₂SH, —CH₂(CH₂)₃NH₂, —CH₂CH₂CH₂NHC(NH)NH₂, phenyl, benzyl,4-hydroxybenzyl, 4-imidazolylmethyl or 3-indolylmethyl or optionally, R⁸and R⁹ together with the atoms to which they are bonded form anazetidine, pyrrolidine or piperidine ring.

In still another embodiment of a compound of Formula (II), n is 1, q is1, R¹⁰ is [R⁵NH(CHR⁴)_(p)C(O)]—, p is 1, and R⁵ is hydrogen to provide acompound of Formula (XVIII):

wherein R³ is hydrogen or methyl, R⁴ is hydrogen, alkanyl, substitutedalkanyl, aryl, substituted aryl, arylalkanyl, substituted arylalkanyl,cycloalkanyl, heteroarylalkanyl or substituted heteroarylalkanyl, R⁸ ishydrogen or methyl and R⁹ is hydrogen, alkanyl, substituted alkanyl,aryl, substituted aryl, arylalkanyl, substituted arylalkanyl,cycloalkanyl, heteroarylalkanyl or substituted heteroarylalkanyl, oroptionally, R⁸ and R⁹ together with the atoms to which they are bonded,form a cycloheteroalkyl or substituted cycloheteroalkyl ring.

In one embodiment of a compound of Formula (XVIII), R⁴ is hydrogen,alkanyl or cycloalkanyl. Preferably, R⁴ is hydrogen, methyl, isopropyl,isobutyl, sec-butyl, t-butyl, cyclopentyl or cyclohexyl. Preferably, R⁸is hydrogen and R⁹ is hydrogen, methyl, isopropyl, isobutyl, sec-butyl,t-butyl, cyclopentyl, cyclohexyl, —CH₂OH, —CH(OH)CH₃, —CH₂CO₂H,—CH₂CH₂CO₂H, —CH₂CONH₂, —CH₂CH₂CONH₂, —CH₂CH₂SCH₃, —CH₂SH,—CH₂(CH₂)₃NH₂, —CH₂CH₂CH₂NHC(NH)NH₂, phenyl, benzyl, 4-hydroxybenzyl,4-imidazolylmethyl or 3-indolylmethyl or optionally, R⁸ and R⁹ togetherwith the atoms to which they are bonded, form an azetidine, pyrrolidineor piperidine ring.

In another embodiment of a compound of Formula (XVIII), R⁴ issubstituted alkanyl. Preferably, R⁴ is —CH₂OH, —CH(OH)CH₃, —CH₂CO₂H,—CH₂CH₂CO₂H, —CH₂CONH₂, —CH₂CH₂CONH₂, —CH₂CH₂SCH₃, —CH₂SH, —CH₂(CH₂)₃NH₂or —CH₂CH₂CH₂NHC(NH)NH₂. Preferably, R⁸ is hydrogen and R⁹ is hydrogen,methyl, isopropyl, isobutyl, sec-butyl, t-butyl, cyclopentyl,cyclohexyl, —CH₂OH, —CH(OH)CH₃, —CH₂CO₂H, —CH₂CH₂CO₂H, —CH₂CONH₂,—CH₂CH₂CONH₂, —CH₂CH₂SCH₃, —CH₂SH, —CH₂(CH₂)₃NH₂, —CH₂CH₂CH₂NHC(NH)NH₂,phenyl benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl or 3-indolylmethyl oroptionally, R⁸ and R⁹ together with the atoms to which they are bonded,form an azetidine, pyrrolidine or piperidine ring.

In still another embodiment of a compound of Formula (XVIII), R⁴ isaryl, arylalkanyl, substituted arylalkanyl or heteroarylalkanyl.Preferably, R⁴ is phenyl, benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl or3-indolylmethyl. Preferably, R⁸ is hydrogen and R⁹ is hydrogen, methyl,isopropyl, isobutyl, sec-butyl, t-butyl, cyclopentyl, cyclohexyl,—CH₂OH, —CH(OH)CH₃, —CH₂CO₂H, —CH₂CH₂CO₂H, —CH₂CONH₂, —CH₂CH₂CONH₂,—CH₂CH₂SCH₃, —CH₂SH, —CH₂(CH₂)₃NH₂, —CH₂CH₂CH₂NHC(NH)NH₂, phenyl,benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl or 3-indolylmethyl, oroptionally, R⁸ and R⁹ together with the atoms to which they are bondedform an azetidine, pyrrolidine or piperidine ring.

In still another embodiment of a compound of Formula (XVIII), theα-carbon of the N-terminal amino acid residue is of the L-configuration.In still another embodiment of a compound of Formula (XVIII), theα-carbon of the N-terminal amino acid residue is of the D-configuration.In still another embodiment of a compound of Formula (XVIII), theα-carbon of the C-terminal amino acid residue is of the L-configuration.In still another embodiment of a compound of Formula (XVIII), theα-carbon of the C-terminal amino acid residue is of the D-configuration.In still another embodiment of a compound of Formula (XVIII), theα-carbons of both the N- and C-terminal amino acid residues are of theL-configuration.

In still another embodiment of a compound of Formula (XVIII), R³ ishydrogen.

Compounds of structural Formulae (I)–(XVIII) may be administered orallyand transported across cells (i.e., enterocytes) lining the lumen of thegastrointestinal tract. While not wishing to be bound by any particulartransport mechanism, some of the compounds of structural Formulae(I)–(XVIII) may be substrates for the proton-coupled intestinal peptidetransport system (“PEPT1”) (Leibach et al., Annu. Rev. Nutr. 1996, 16,99–119) which, typically mediates the cellular uptake of small intactpeptides consisting of two or three amino acids that are derived fromthe digestion of dietary proteins. In the intestine, where smallpeptides are not effectively absorbed by passive diffusion, PEPT1 mayact as a vehicle for their effective uptake across the apical membraneof the gastric mucosa.

Methods for determining whether compounds of Formulae (I)–(XVIII) serveas substrates for the PEPT1 transporter are disclosed in Example 131herein (see Section 5). In vitro systems, which use cells engineered toheterologously express the transport system, or cell-lines thatendogenously express the transporter (e.g. Caco-2 cells) may be used toassay transport of compounds of Formulae (I)–(XVIII) by PEPT1transporter. Standard methods for evaluating the enzymatic conversion ofpropofol prodrug compounds to propofol in vitro are disclosed in Example132 herein.

Oral administration of propofol prodrug compounds to rats and monkeys isdescribed in Examples 134 and 135 respectively.

4.3 Synthesis of Propofol Prodrug Compounds

The compounds of Formulae (I)–(XVIII) may be obtained via the syntheticmethods illustrated in Schemes 1–10. Starting materials useful forpreparing these compounds and intermediates thereof are commerciallyavailable or can be prepared by well-known synthetic methods (Harrisonet al., “Compendium of Synthetic Organic Methods”, Vols. 1–8 (John Wileyand Sons, 1971–1996); “Beilstein Handbook of Organic Chemistry,”Beilstein Institute of Organic Chemistry, Frankfurt, Germany; Feiser etal, “Reagents for Organic Synthesis,” Volumes 1–17, Wiley Interscience;Trost et al., “Comprehensive Organic Synthesis,” Pergamon Press, 1991;“Theilheimer's Synthetic Methods of Organic Chemistry,” Volumes 1–45,Karger, 1991; March, “Advanced Organic Chemistry,” Wiley Interscience,1991; Larock “Comprehensive Organic Transformations,” VCH Publishers,1989; Paquette, “Encyclopedia of Reagents for Organic Synthesis,” JohnWiley & Sons, 1995). Other methods for synthesis of the compoundsdescribed herein and/or starting materials are either described in theart or will be readily apparent to the skilled artisan. Accordingly, themethods presented in Schemes 1–10 herein are illustrative rather thancomprehensive.

Certain amino acid building blocks useful for the preparation ofcompounds of Formula (I) are illustrated in Scheme 1. Amino acids ofeither L- or D-stereochemistry may be used in these reactions. Compound(2) is a protected aspartic or glutamic acid residue, where theprotecting groups Pg¹ and Pg² are removable under orthogonal conditions.Non-limiting Examples of useful protecting groups for the nitrogen atominclude tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (CBz) and9-fluorenylmethyloxycarbonyl (Fmoc) moieties, while those for thecarboxyl group include tert-butyl, benzyl and 9-fluorenylmethyl esters.Nitrogen protected amino acid residues may be conveniently activated forcoupling via conversion to their NHS esters, as illustrated by thepreparation of compounds (7) and (8).

A method for preparing a compound of Formula (I) where n is 0, m is 1 or2, X is a bond, R¹ is [H₂N(CHR)C(O)]— and R² is OH, i.e., compound (10),is illustrated in Scheme 2. Compound (4) is reacted either with activeester (7) or protected amino acid (6) in the presence of a peptidecoupling agent to afford intermediate (9), which upon deprotectionyields compound (10).

In a similar fashion, a method for preparing a compound of Formula (I)where n is 0, m is 1 or 2, X is a bond, R¹ is hydrogen and R² is—[NH(CHR)C(O)OH], i.e., compound (13), is illustrated in Scheme 3.Compound (11) is reacted either with active ester (8) or protected aminoacid (5) in the presence of a peptide coupling agent to affordintermediate (12), which upon deprotection yields compound (13).

Compounds of Formula (I) may also be prepared via solid-phase synthesismethods, as is illustrated in Scheme 4 below for the preparation ofcompounds (10) and (13).

Compounds of Formula (I) where n is 0, m is 1, X is O, R¹ is[H₂N(CHR)C(O)]— and R² is OH, i.e., compound (18), may be prepared bymethods illustrated in Scheme 5. Propofol is converted to thechloroformate derivative (16) by treatment with a phosgene equivalentand then reacted with serine dipeptide (17). Deprotection affords thepropofol carbonate compound (18).

Compounds of Formula (I) where n is 1, m is 1 or 2, X is a bond, R¹ is[H₂N(CHR)C(O)]— and R² is OH, i.e., compound (23), may be prepared bymethods illustrated in Scheme 6. The protected aspartate or glutamatedipeptide (19) is treated with the gem-dialkylating agent (20) in thepresence of a base or metal promoter agent (typically a soluble Ag⁺ orHg²⁺ salt) to afford intermediate (21). Displacement of the secondleaving group X₂ from (21) by propofol generates acyloxyalkyl ether(22), which upon deprotection affords the desired compound (23). If X₂in (27) is SR (e.g., thiomethyl), activation by treatment with sulfurylchloride or similar halogenating agent precedes displacement by propofolto generate compound (22).

Alternatively, compound (22) may be prepared by first generating thehaloalkyl (or thioalkyl) propofol ether (24), then displacing theleaving group X₂ with the carboxylate anion of dipeptide (19), as shownin Scheme 7.

In an analogous manner, compounds of Formula (I) where n is 1, m is 1 or2, X is a bond, R¹ is hydrogen, and R² is —[NH(CHR)C(O)OH], i.e.,compound (28), may be prepared as illustrated in Scheme 8.

Compounds of Formula (II) where n is 0, q is 1, and R¹⁰ is[H₂N(CHR)C(O)]—, i.e., compound (30), may be prepared according tomethods illustrated in Scheme 9.

Compounds of Formula (II) where n is 1, q is 1, and R¹⁰ is hydrogen,i.e., compound (33), and where n is 1, q is 1, and R¹⁰ is[H₂N(CHR)C(O)]—, i.e., compound (34), may be prepared according tomethods illustrated in Scheme 10. Synthesis of intermediate (32)proceeds either via haloalkyl ester (31) or haloalkyl ether (24) aspreviously described.

4.4 Therapeutic/Prophylactic Uses and Methods of Administration

The compounds of Formulae (I)–(XVIII), as described herein, may be usedto treat and/or prevent migraine in patients. The methods compriseadministering to a patient a therapeutically effective amount of acompound of Formulae (I)–(XVIII) to treat and/or prevent migraine. Inthe therapeutic methods herein, a therapeutically effective amount ofthe compound is administered to a patient suffering from a migraineheadache. In the prophylactic methods herein, a therapeuticallyeffective amount of the compound is administered to a patient at risk ofdeveloping a migraine.

In one embodiment, the compounds are administered orally to treat and/orprevent migraine. However, in other embodiments, the compounds areadministered parenterally (e.g., via inhalation or injection). In oneembodiment, the compounds are administered in amounts of between about10 mg to about 4 g to treat or prevent migraine.

The compounds of Formulae (I)–(XVIII) may also be used as anti-emeticsand can be administered to patients at risk of vomiting and/or who arenauseous. For Example, the compounds may be administered to patientsthat are being concurrently treated with various chemotherapy agentsand/or surgical procedures, which induce nausea, in order to treatand/or prevent nausea and vomiting. Typically, a therapeuticallyeffective amount of the compound is administered to a patient to treatand/or prevent nausea and vomiting.

In one embodiment, the compounds are administered orally to treat and/orprevent nausea or vomiting. However, in other embodiments, the compoundsare administered parenterally (e.g., via inhalation or injection totreat and/or prevent nausea or vomiting. In one embodiment, thecompounds are administered in amounts of between about 10 mg to about 4g to treat and/or prevent nausea or vomiting.

The compounds of Formulae (I)–(XVIII) may also be used as hypnoticagents to induce and/or maintain general anesthesia and/or as asedative. Typically, a therapeutically effective amount of the compoundis administered to a patient to induce hypnosis, anesthesia and/orsedation.

In one embodiment, the compounds are administered intravenously whenused as a general anesthetic. In another embodiment, the compounds areadministered by inhalation. The compounds may be formulated by methodsused to formulate propofol, which are well known in the art. In oneembodiment, compounds of Formulae (I)–(XVIII) that are water soluble maybe formulated as an injectable aqueous solution, which containssignificantly less emulsifiers or solubilizers than used in aqueousformulations of propofol, thereby avoiding discomfort at the site ofinjection.

In one embodiment, the compounds are administered orally in amounts ofabout 10 mg to 4 g daily when used as a sedative (e.g., for thetreatment of anxiety conditions). However, in another embodiment, thecompounds may also be administered by inhalation, intravenously orintramuscularly when used as a sedative.

The compounds of Formulae (I)–(XVIII) may be administered in similaramounts and in the same schedule as described in the art for propofol.In one embodiment, dosage levels of the compounds of Formulae(I)–(XVIII) for producing general anesthesia, maintaining anesthesia andproducing a sedative effect are as described in the art for propofol.

The compounds of Formulae (I)–(XVIII) may also be used to inhibitoxidation in biological materials. The methods involve contacting thebiological material with an effective amount of the compound. Intherapeutic methods herein, a therapeutically effective amount of thecompound is administered to a patient suffering from a pathologicalcondition treated by inhibition of oxidation. In prophylactic methodsherein, a therapeutically effective amount of the compound isadministered to a patient at risk of developing a disease as a result ofexposure to oxidative stress. The compounds may find particular use inpreventing and/or treating oxidation in disorders of the central nervoussystem that involve an inflammatory component.

The compounds of Formulae (I)–(XVIII) may be used to treat and/orprevent neurodegenerative conditions of the nervous system, whichinclude, but are not limited to, Friedrich's disease, Parkinson'sdisease, Alzheimer's disease, Huntington's disease, amyotrophic lateralsclerosis (ALS), multiple sclerosis (MS) and Pick disease. In oneembodiment, a therapeutically effective amount of a compound (e.g.,between about 10 mg to about 4 g daily) is orally administered to treatand/or prevent chronic neurodegenerative diseases.

The compounds of Formulae (I)–(XVIII) may also be used to treat and/orprevent trauma to the central nervous system such as, for Example, skullfracture and its resulting edema, concussion, contusion, brainhemorrhages, shearing lesions, subdural and epidural hematoma, andspinal cord injury (e.g., mechanical injury due to compression orflexion of the spinal cord). In one embodiment, a compound isparenterally administered by intravenous injection or injection directlyinto the central nervous system (i.e., intrathecally (“IT”) or into thebrain) to treat and/or prevent traumatic conditions of the centralnervous system. In another embodiment, a therapeutically effectiveamount of a compound (e.g., between about 25 mg to about 500 mg IV or IMand between about 5 mg to about 100 mg IT) are administered to treatand/or prevent traumatic conditions of the central nervous system.

The compounds of Formulae (I)–(XVIII) may also be used asanti-convulsives to treat and/or prevent seizures (e.g., epilepticseizures). Methods for treating and/or preventing convulsions compriseadministering a therapeutically effective amount of a compound to apatient in need of such treatment. In one embodiment, the compounds areadministered orally to treat and/or prevent convulsions. In anotherembodiment, the compounds are parenterally administered to treat and/orprevent convulsions. In still another embodiment, the compounds areadministered in amounts of between about 10 mg to about 4 g daily totreat and/or prevent convulsions.

When used to treat and/or prevent the above disease or disorderscompounds and/or pharmaceutical compositions of Formulae (I)–(XVIII) maybe administered or applied singly, or in combination with other agents.The compounds and/or compositions may also be administered or appliedsingly, or in combination with other pharmaceutically active agents,including other compounds of Formulae (I)–(XVIII).

Provided herein are methods of treatment and prophylaxis byadministering to a patient a therapeutically effective amount of acomposition or compound of Formulae (I)–(XVIII). The patient may be ananimal, is more preferably, a mammal and even more preferably, a human.

The compounds of Formulae (I)–(XVIII) and/or pharmaceutical compositionsthereof are preferably administered orally. The compounds and/orpharmaceutical compositions thereof may also be administered by anyother convenient route, for Example, by infusion or bolus injection, byabsorption through epithelial or mucocutaneous linings (e.g., oralmucosa, rectal and intestinal mucosa, etc.). Administration can besystemic or local. Various delivery systems are known, (e.g.,encapsulation in liposomes, microparticles, microcapsules, capsules,etc.) that can be used to administer a compound and/or pharmaceuticalcomposition. Methods of administration include, but are not limited to,intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous,intranasal, epidural, oral, sublingual, intranasal, intracerebral,intravaginal, transdermal, rectally, by inhalation, or topically,particularly to the ears, nose, eyes, or skin.

In specific embodiments, it may be desirable to administer one or morecompounds and/or pharmaceutical compositions thereof locally to the areain need of treatment. This may be achieved, for Example, and not by wayof limitation, by local infusion during surgery, topical application,e.g., in conjunction with a wound dressing after surgery, by injection,by means of a catheter, by means of a suppository, or by means of animplant, said implant being of a porous, non-porous, or gelatinousmaterial, including membranes, such as sialastic membranes or fibers. Inone embodiment, administration can be by direct injection at the site(or former site) of cancer or arthritis.

In certain embodiments, it may be desirable to introduce one or morecompounds and/or pharmaceutical compositions thereof into the centralnervous system by any suitable route, including intraventricular,intrathecal and epidural injection. Intraventricular injection may befacilitated by an intraventricular catheter, for Example, attached to areservoir, such as an Ommaya reservoir.

In one embodiment, the compounds and/or pharmaceutical compositions canbe delivered via sustained release systems, preferably oral sustainedrelease systems. In one embodiment, a pump may be used (Langer, supra;Sefton, 1987, CRC Crit Ref Biomed Eng. 14:201; Saudek et al., 1989, N.Engl. J. Med. 321:574).

In another embodiment, polymeric materials can be used (see “MedicalApplications of Controlled Release,” Langer and Wise (eds.), CRC Pres.,Boca Raton, Fla. (1974); “Controlled Drug Bioavailability,” Drug ProductDesign and Performance, Smolen and Ball (eds.), Wiley, New York (1984);Langer et al., 1983, J Macromol. Sci. Rev. Macromol Chem. 23:61; Levy etal., 1985, Science 228: 190; During et al., 1989, Ann. Neurol. 25:351;Howard et al., 1989, J. Neurosurg. 71:105).

In still another embodiment, polymeric materials are used for oralsustained release delivery. Preferred polymers include sodiumcarboxymethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose and hydroxyethylcellulose (most preferred,hydroxypropylmethylcellulose). Other preferred cellulose ethers havebeen described (Alderman, Int. J. Pharm. Tech. & Prod. Mfr. 1984, 5(3)1–9). Factors affecting drug release are well known to the skilledartisan and have been described in the art (Bamba et al., Int. J. Pharm.1979, 2, 307).

In still another embodiment, enteric-coated preparations can be used fororal sustained release administration. Preferred coating materialsinclude polymers with a pH-dependent solubility (i.e., pH-controlledrelease), polymers with a slow or pH-dependent rate of swelling,dissolution or erosion (i.e., time-controlled release), polymers thatare degraded by enzymes (i.e., enzyme-controlled release) and polymersthat form firm layers that are destroyed by an increase in pressure(i.e., pressure-controlled release).

In still another embodiment, osmotic delivery systems are used for oralsustained release administration (Verma et al., Drug Dev. Ind. Pharm.2000, 26:695–708). In a preferred embodiment, OROS™ osmotic devices areused for oral sustained release delivery devices (Theeuwes et al., U.S.Pat. No. 3,845,770; Theeuwes et al., U.S. Pat. No. 3,916,899).

For administration by inhalation, a compound may be convenientlydelivered to the lung by a number of different devices. For Example, aMetered Dose Inhaler (“MDI”) which utilizes canisters that contain asuitable low boiling propellant, e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas may be used to deliver compounds directly to thelung.

Alternatively, a Dry Powder Inhaler (“DPI)” device may be used toadminister a compound to the lung (See, e.g., Raleigh et al., Proc.Amer. Assoc. Cancer Research Annual Meeting 1999, 40, 397). DPI devicestypically use a mechanism such as a burst of gas to create a cloud ofdry powder inside a container, which may then be inhaled by the patientand are well known in the art and may be purchased from a number ofcommercial sources. A popular variation is the multiple dose DPI(“MDDPI”) system, which allows for the delivery of more than onetherapeutic dose. For Example, capsules and cartridges of gelatin foruse in an inhaler or insufflator may be formulated containing a powdermix of a compound and a suitable powder base such as lactose or starchfor these systems.

Another type of device that may be used to deliver a compound to thelung is a liquid spray device supplied, for Example, by AradigmCorporation, Hayward, Calif. Liquid spray systems use extremely smallnozzle holes to aerosolize liquid drug formulations that may then bedirectly inhaled into the lung.

In one embodiment, a nebulizer device is used to deliver a compound tothe lung. Nebulizers create aerosols from liquid drug formulations byusing, for Example, ultrasonic energy to form fine particles that may bereadily inhaled (e.g., Verschoyle et al., British J Cancer 1999, 80,Suppl. 2, 96; Armer et al., U.S. Pat. No. 5,954,047; van der Linden etal., U.S. Pat. No. 5,950,619; van der Linden et al., U.S. Pat. No.5,970,974).

In another embodiment, an electrohydrodynamic (“EHD”) aerosol device isused to deliver a compound to the lung. EHD aerosol devices useelectrical energy to aerosolize liquid drug solutions or suspensions(see e.g., Noakes et al., U.S. Pat. No. 4,765,539; Coffee, U.S. Pat. No.4,962,885; Coffee, International Publication No., WO 94/12285; Coffee,International Publication No., WO 94/14543; Coffee, InternationalPublication No., WO 95/26234, Coffee, International Publication No., WO95/26235, Coffee, International Publication No., WO 95/32807). Theelectrochemical properties of a compound may be important parameters tooptimize when delivering the compound to the lung with an EHD aerosoldevice, and such optimization is routinely performed by one of skill inthe art. EHD aerosol devices may more efficiently deliver drugs to thelung than existing pulmonary delivery technologies. Other methods ofintra-pulmonary delivery of a compound will be known to the skilledartisan.

The compounds of Formulae (I)–(XVIII) and/or compositions containingsuch compounds preferably provide therapeutic or prophylactic levels ofpropofol upon in vivo administration to a patient. While not wishing tobound by theory, the promoiety or promoieties of the compounds may becleaved either chemically and/or enzymatically. One or more enzymespresent in the stomach, intestinal lumen, intestinal tissue, blood,liver, brain or any other suitable tissue of a mammal may enzymaticallycleave the promoiety or promoieties of the administered compounds.

While not wishing to bound by theory, the promoiety or promoieties ofthe compounds may be cleaved prior to absorption by the gastrointestinaltract (e.g., within the stomach or intestinal lumen) and/or afterabsorption by the gastrointestinal tract (e.g., in intestinal tissue,blood, liver or other suitable tissue of a mammal). Preferably, propofolremains conjugated to a promoiety during transit across the intestinalmucosal barrier to provide protection from presystemic metabolism. Inone embodiment, the compounds are essentially not metabolized topropofol within enterocytes, but are metabolized to the parent drugwithin the systemic circulation. Cleavage of the promoiety orpromoieties of the compounds after absorption by the gastrointestinaltract may allow these prodrugs to be absorbed into the systemiccirculation either by active transport, passive diffusion or by amixture of both active and passive processes. In one embodiment, thecompounds are actively absorbed through interaction with the intestinalpeptide transporter PEPT1.

Cleavage of the promoiety or promoieties of the compounds of Formulae(I)–(XVIII) after absorption by the gastrointestinal tract, may allowthese prodrugs to be absorbed into the systemic circulation from thelarge intestine. In one embodiment, the compounds and/or pharmaceuticalcompositions containing compounds of Formulae (I)–(XVIII) are preferablyadministered as sustained release systems. In another embodiment, thecompounds and/or pharmaceutical compositions are delivered by oralsustained release administration. Preferably, in this embodiment, thecompounds and/or pharmaceutical compositions are administered twice perday (more preferably, once per day).

4.5 Pharmaceutical Compositions

The present pharmaceutical compositions contain a therapeuticallyeffective amount of one or more compounds of Formulae (I)–(XVIII),preferably, in purified form, together with a suitable amount of apharmaceutically acceptable vehicle, so as to provide the form forproper administration to a patient. When administered intravenously to apatient, the compounds and pharmaceutically acceptable vehicles arepreferably sterile. Water is a preferred vehicle when a compound isadministered intravenously. Saline solutions and aqueous dextrose andglycerol solutions can also be employed as liquid vehicles, particularlyfor injectable solutions. Suitable pharmaceutical vehicles also includeexcipients such as starch, glucose, lactose, sucrose, gelatin, malt,rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate,talc, sodium chloride, dried skim milk, glycerol, propylene, glycol,water, ethanol and the like. The present compositions, if desired, canalso contain minor amounts of wetting or emulsifying agents, or pHbuffering agents. In addition, auxiliary, stabilizing, thickening,lubricating and coloring agents may be used.

Pharmaceutical compositions comprising a compound of Formulae(I)–(XVIII) may be manufactured by means of conventional mixing,dissolving, granulating, dragee-making, levigating, emulsifying,encapsulating, entrapping or lyophilizing processes. Pharmaceuticalcompositions may be formulated in conventional manner using one or morephysiologically acceptable carriers, diluents, excipients orauxiliaries, which facilitate processing of compounds into preparationswhich can be used pharmaceutically. Proper formulation is dependent uponthe route of administration chosen.

The present pharmaceutical compositions can take the form of solutions,suspensions, emulsion, tablets, pills, pellets, capsules, capsulescontaining liquids, powders, sustained-release formulations,suppositories, emulsions, aerosols, sprays, suspensions, or any otherform suitable for use. In one embodiment, the pharmaceuticallyacceptable vehicle is a capsule (see e.g., Grosswald et al., U.S. Pat.No. 5,698,155). Other Examples of suitable pharmaceutical vehicles havebeen described in the art (see Remington's Pharmaceutical Sciences,Philadelphia College of Pharmacy and Science, 19th Edition, 1995).Preferred pharmaceutical compositions are formulated for oral delivery.

Pharmaceutical compositions for oral delivery may be in the form oftablets, lozenges, aqueous or oily suspensions, granules, powders,emulsions, capsules, syrups, or elixirs, for Example. Orallyadministered pharmaceutical compositions may contain one or moreoptional agents, for Example, sweetening agents such as fructose,aspartame or saccharin, flavoring agents such as peppermint, oil ofwintergreen, or cherry coloring agents and preserving agents, to providea pharmaceutically palatable preparation. Moreover, where in tablet orpill form, the pharmaceutical compositions may be coated to delaydisintegration and absorption in the gastrointestinal tract, therebyproviding a sustained action over an extended period of time.Selectively permeable membranes surrounding an osmotically activedriving compound are also suitable for orally administered compounds andpharmaceutical compositions. In these later platforms, fluid from theenvironment surrounding the capsule is imbibed by the driving compound,which swells to displace the agent or agent composition through anaperture. These delivery platforms can provide an essentially zero orderdelivery profile as opposed to the spiked profiles of immediate releaseformulations. A time delay material such as glycerol monostearate orglycerol stearate may also be used. Oral pharmaceutical compositions caninclude standard vehicles such as mannitol, lactose, starch, magnesiumstearate, sodium saccharine, cellulose, magnesium carbonate, etc. Suchvehicles are preferably of pharmaceutical grade.

For oral liquid preparations such as, for Example, suspensions, elixirsand solutions, suitable carriers, excipients or diluents include water,saline, alkyleneglycols (e.g., propylene glycol), polyalkylene glycols(e.g., polyethylene glycol) oils, alcohols, slightly acidic buffersbetween pH 4 and pH 6 (e.g., acetate, citrate, ascorbate at betweenabout 5 mM to about 50 mM), etc. Additionally, flavoring agents,preservatives, coloring agents, bile salts, acylcarnitines and the likemay be added.

A compound of Formulae (I)–(XVIII) may also be formulated in rectal orvaginal pharmaceutical compositions such as suppositories or retentionenemas, e.g., containing conventional suppository bases such as cocoabutter or other glycerides.

In addition to the formulations described previously, a compound ofFormulae (I)–(XVIII) may also be formulated as a depot preparation. Suchlong acting formulations may be administered by implantation (forExample subcutaneously or intramuscularly) or by intramuscularinjection. Thus, for Example, a compound may be formulated with suitablepolymeric or hydrophobic materials (for Example as an emulsion in anacceptable oil) or ion exchange resins, or as sparingly solublederivatives, for Example, as a sparingly soluble salt.

When a compound of Formulae (I)–(XVIII) is acidic, it may be included inany of the above-described formulations as the free acid, apharmaceutically acceptable salt, a solvate, hydrate or N-oxide.Pharmaceutically acceptable salts substantially retain the activity ofthe free acid, may be prepared by reaction with bases and tend to bemore soluble in aqueous and other protic solvents than the correspondingfree acid form.

Liquid drug formulations suitable for use with nebulizers and liquidspray devices and EHD aerosol devices will typically include a compoundwith a pharmaceutically acceptable carrier. Preferably, thepharmaceutically acceptable carrier is a liquid such as alcohol, water,polyethylene glycol or a perfluorocarbon. Optionally, another materialmay be added to alter the aerosol properties of the solution orsuspension of the compounds. Preferably, this material is liquid such asan alcohol, glycol, polyglycol or a fatty acid. Other methods offormulating liquid drug solutions or suspension suitable for use inaerosol devices are known to those of skill in the art (e.g., Biesalski,U.S. Pat. No. 5,112,598; Biesalski, U.S. Pat. No. 5,556,611).

4.6 Combination Therapy

In certain embodiments, the compounds of Formulae I)–(XVIII) can be usedin combination therapy with at least one other therapeutic agent. Thecompound and the other therapeutic agent(s) can act additively or, morepreferably, synergistically. In a preferred embodiment, a compositioncomprising a propofol prodrug compound is administered concurrently withthe administration of another therapeutic agent, such as for Example,another sedative, hypnotic agent or anesthetic agent (e.g., propofol),which can be part of the same composition as the propofol prodrugcompound or a different composition. In another embodiment, acomposition comprising a propofol prodrug compound is administered prioror subsequent to administration of another therapeutic agent, such as,for Example, another sedative, hypnotic agent or anesthetic agent,(e.g., propofol).

5. EXAMPLES

The invention is further defined by reference to the following Examples,which describe preparation of compounds of Formulae (I)–(XVIII),compositions containing such compounds and assays for using suchcompounds and compositions. It will be apparent to those skilled in theart that many modifications, both to materials and methods, may bepracticed without departing from the scope of the invention.

In the Examples below, the following abbreviations have the followingmeanings. If an abbreviation is not defined, it has its generallyaccepted meaning.

Aib = α-aminoisobutyric acid Atm = atmosphere Boc =tert-butyloxycarbonyl Bzl = benzyl Cbz = carbobenzyloxy Dap =L-2,3-diaminopropionic acid DCC = dicyclohexylcarbodiimide DMAP =4-N,N-dimethylaminopyridine DMEM = Dulbecco's minimun eagle medium DMF =N,N-dimethylformamide DMSO = dimethylsulfoxide Fmoc =9-fluorenylmethyloxycarbonyl g = gram h = hour HBSS = Hank's bufferedsaline solution L = liter LC/MS = liquid chromatography/massspectroscopy M = molar min = minute mL = milliliter mmol = millimolesNHS = N-hydroxysuccinimide PBS = phosphate buffered saline THF =tetrahydrofuran TFA = trifluoroacetic acid TMS = trimethylsilyl μL =microliter μM = micromolar v/v = volume to volume

Example 1 Boc-Asp(OPropofol)-OBzl (101)

To a homogeneous solution of Boc-Asp-OBzl (322 mg, 1.0 mmol), DMAP (12mg, 0.1 mmol) and propofol (175 μL, 0.9 mmol) in tetrahydrofuran (3.5mL) at room temperature was added dicyclohexylcarbodiimide (308 mg, 1.5mmol). After stirring for 4 h, the dicyclohexylurea was filtered off andthe solution was diluted with ether (100 mL). The ether layer was washedwith 10% citric acid (2×25 mL), saturated sodium bicarbonate (2×25 mL),and brine (2×25 mL). The organic layer was dried over Na₂SO₄ and thenconcentrated in vacuo. The crude compound was purified by chromatographyon silica gel (Biotage), eluting with a gradient of hexane to 10%EtOAc/hexane) to afford the title compound (101) (400 mg, 83% yield).¹H-NMR (400 MHz, CD₃OD): δ 7.34 (m, 5H), 7.16 (m, 3H), 5.20 (d, J=1.6Hz, 2H), 4.68 (dd, J₁=5.6, 7.6 Hz, 1H), 3.30 (m, 1H), 3.13 (dd, J=7.6,16.8 Hz, 1H), 2.93 (m, 2H), 1.44 (s, 9H), 1.1 (d, J=7.2 Hz, 12H); MS(ESI) m/z 506.34 (M+Na⁺).

H-Asp(OPropofol)-OBzl (102)

Compound (101) was treated with 30% TFA (30 mL) in dichloromethane (70mL) for 30 min and the solvent removed in vacuo to afford the titlecompound, which was used in subsequent reactions without furtherpurification. MS (ESI) m/z 385.85 (M+H⁺).

Boc-Asp(OPropofol)-OH (103)

To a flask containing 500 mg of 10% Pd—C was added a solution ofcompound (101) in methanol under nitrogen. The resulting mixture wasdegassed three times, after which hydrogen was introduced via a balloonapparatus. The suspended mixture was allowed to stir vigorously for 4 h.The reaction mixture was filtered through a pad of celite andconcentrated in vacuo to arrive at the title compound, which was used insubsequent reactions without further purification. MS (ESI) m/z 392.32(M−H⁺).

Boc-Glu(OPropofol)-OBzl (104)

To a homogeneous solution of Boc-Glu-OBzl (7.20 g, 0.213 mol), DMAP(0.261 g, 0.021 mol) and propofol (3.76 mL, 0.20 mol) in tetrahydrofuran(40 mL) at room temperature was added dicyclohexylcarbodiimide (5.72 g,0.278 mol). After stirring for 4 h, the dicyclohexylurea was filteredoff and the solution was diluted with ether (250 mL). The ether layerwas washed with 10% citric acid (2×100 mL), saturated sodium bicarbonate(2×100 mL), and brine (2×100 mL). The organic layer was dried overNa₂SO₄ and then concentrated in vacuo. The crude compound was purifiedby chromatography on silica gel (Biotage), eluting with a gradient ofhexane to 10% EtOAc/hexane, to afford the title compound (8.20 g, 77%yield). ¹H-NMR (400 MHz, CDCl₃): δ 7.36 (m, 5H), 7.15 (m, 3H), 5.21 (m,2H), 4.45 (m, 1H), 2.89–2.75 (m, 2H), 2.74–2.63 (m, 2H), 2.34 (m, 1H),2.10 (m, 1H), 1.46 (s, 9H), 1.18 (d, J=6.8 Hz, 12H). MS (ESI) m/z 521.36(M+Na⁺).

H-Glu(OPropofol)-OBzl (105)

Compound (104) was treated with 30% TFA (45 mL) in dichloromethane (105mL) to arrive at the title compound (105), which was used in subsequentreactions without further purification. MS (ESI) m/z 398.37 (M+H⁺).

Boc-Glu(OPropofol)-OH (106)

To a flask containing 500 mg of 10% Pd—C was added a solution ofcompound (104) in methanol under nitrogen. The resulting mixture wasdegassed three times, after which hydrogen was introduced via a balloonapparatus. The suspended mixture was allowed to stir vigorously for 4 h.The reaction mixture was filtered through a pad of celite andconcentrated in vacuo to arrive at the title compound, which was used infollowing reactions without further purification. MS (ESI) m/z 407.31(M−H⁺).

Example 2 H-Ala-Asp(OPropofol)-OH (107)

To a homogeneous solution of CBz-Ala-OH (601 mg, 2.7 mmol) inacetonitrile (5 mL) was added DCC (667 mg, 3.2 mmol).N-Hydroxysuccinimide (434 mg, 3.8 mmol) was then added and the reactionwas allowed to proceed at room temperature for 4 h. The resultingdicyclohexylurea was filtered and to the filtrate was added compound(102) (1.03 g, 2.7 mmol). Triethylamine (5 mL) was added and afterstirring for 6 h, the solution was extracted with ethyl acetate (200mL), washed with 10% citric acid (2×50 mL), saturated sodium bicarbonate(2×50 mL) and brine (2×50 mL). The organic layer was dried over Na₂SO₄and then concentrated in vacuo. The crude compound was purified bychromatography on silica gel (Biotage), eluting with a gradient ofhexane to 20% EtOAc/hexane) then the eluant was concentrated in vacuo toafford a white solid. This product was dissolved in a solution of 50%ethyl acetate:hexanes and added to a flask containing 100 mg of 10% Pd—Cunder nitrogen. The resulting mixture was degassed three times, thenhydrogen was introduced via a balloon apparatus. The suspended solutionwas allowed to stir vigorously for 12 h. The reaction mixture wasfiltered through a pad of celite, concentrated in vacuo, and purified bypreparative LC/MS to afford the title compound (107) (422 mg, 43%yield). ¹H-NMR (400 MHz, CD₃OD): δ 7.16 (m, 3H), 4.63 (dd, J=4.8, 7.2 Hz1H), 3.90 (q, J=7.2, 1H), 3.28–3.16 (m, 2H), 2.97 (m, 2H), 1.55 (d,J=7.2 Hz 3H), 1.18 (d, J=6.8 Hz, 12H). MS (ESI) m/z 365.32 (M+H⁺).

Example 3 H-Phe-Asp(OPropofol)-OH (108)

Following procedures for preparation of compound (107), and substitutingCBz-Phe-OH for CBz-Ala-OH, provided the title compound (108). MS (ESI)m/z 441.32 (M+H⁺).

Example 4 H-β-Ala-Asp(OPropofol)-OH (109)

Following procedures for preparation of compound (107), and substitutingCBz-β-Ala-OH for CBz-Ala-OH, provided the title compound (109). MS (ESI)m/z 365.32 (M+H⁺).

Example 5 H-Abu-Asp(OPropofol)-OH (110)

Following procedures for preparation of compound (107), and substitutingN-CBz-2-aminobutyric acid for CBz-Ala-OH, provided the title compound(110). MS (ESI) m/z 379.40 (M+H⁺).

Example 6 H-Orn-Asp(OPropofol)-OH (111)

Following procedures for preparation of compound (107), and substitutingα-N-CBz-δ-N-CBz-ornithine for CBz-Ala-OH, provided the title compound(111). MS (ESI) m/z 408.33 (M+H⁺).

Example 7 H-NVal-Asp(OPropofol)-OH (112)

Following procedures for preparation of compound (107), and substitutingCBz-norvaline for CBz-Ala-OH, provided the title compound (112). MS(ESI) m/z 393.48 (M+H⁺).

Example 8 H-Sar-Asp(OPropofol)-OH (113)

Following procedures for preparation of compound (107), and substitutingCBz-Sar-OH for CBz-Ala-OH, provided the title compound (113). MS (ESI)m/z 388.27 (M+Na⁺).

Example 9 Preparation of H-Asp(OPropofol)-O-Trityl Resin (114)

To a suspension of 2-chlorotrityl resin (4.1 g, loading 1.69 mmol/g) andFmoc-Asp(OPropofol)-OH (14.7 mmol) in DMF (50 mL) was addeddiisopropylethylamine (5.1 mL, 29.8 mmol) and O-(1H-benzotriazol-1-yl)N,N,N′,N′-tetramethyluronium hexafluoro-phosphate (5.6 g, 14.7 mmol).The resulting reaction mixture was shaken at room temperature for 12 h.The resin was filtered and washed with DMF (3×50 mL), methanol (3×50mL), and dichloromethane (3×50 mL). A 20% v/v piperidine/DMF solution(50 mL) was then added to the resin and after shaking for 1 h at roomtemperature, the resin was filtered, washed with DMF (3×50 mL), methanol(3×50 mL), and dichloromethane (3×50 mL), then allowed to dry in adesiccators over 24 h. The title resin was obtained and carried throughsubsequent steps.

Example 10 H-Asn-Asp(OPropofol)-OH (115)

To a suspension of the resin (114) (650 mg, loading 1.3 mmol/g) in DMF(8 mL) was added a homogeneous solution containing Boc-Asn-OH (392 mg,1.7 mmol) diisopropylethylamine (0.43 mL, 4.5 mmol) andO-(1H-Benzotriazol-1-yl) N,N,N′,N′-tetramethyluroniumhexafluorophosphate (642 mg, 1.7 mmol) in DMF. The reaction mixture wasshaken for 12 h, then the resin was filtered and rinsed with DMF (3×15mL), methanol (3×15 mL), and dichloromethane (3×15 mL). The resin wassoaked in 75% TFA (11 mL) in CH₂Cl₂ (4 mL) for 6 h. The resin was washedwith CH₂Cl₂ and the combined filtrate was collected, concentrated invacuo and purified by preparative LC/MS to afford 54 mg of the titlecompound (115). ¹H-NMR (400 MHz, CD₃OD): 7.16 (m, 3H), 4.71 (dd, J=4.4,7.2 Hz 1H), 4.16 (dd, J=3.6, 9.6 Hz, 1H), 3.29–3.24 (dd, J=4.8, 17.2 Hz1H), 3.17–3.11 (dd, J=7.6, 17.6 Hz, 1H), 3.06–2.95 (m, 2H), 2.77–2.70(dd, J=9.6, 16.8 Hz 1H), 1.19 (d, J=6.4 Hz, 12H): MS (ESI) m/z 408.67(M+H⁺).

Example 11 H-Arg-Asp(OPropofol)-OH (116)

Following procedures for preparation of compound (115), and substitutingBoc-Arg(Mtr)-OH for Boc-Asn-OH, and in the final step soaking the resinin 95% TFA (14 mL) and dichloromethane (0.8 mL) for 12 h, provided thetitle compound (116). MS (ESI) m/z 451.50 (M+H⁺).

Example 12 H-Asp-Asp(OPropofol)-OH (117)

Following procedures for preparation of compound (115), and substitutingBoc-Asp(O^(t)Bu)-OH for Boc-Asn-OH, provided the title compound (117).MS (ESI) m/z 409.31 (M+H⁺).

Example 13 H-Cys-Asp(OPropofol)-OH (118)

Following procedures for preparation of compound (115), and substitutingBoc-Cys(STrt)-OH for Boc-Asn-OH, and in the final step soaking the resinin 95% TFA (14 mL), dichloromethane (0.5 mL) and 1% triisopropylsilane(0.5 mL) for 6 h provided the title compound (118). MS (ESI) m/z 397.39(M+H⁺).

Example 14 H-Leu-Asp(OPropofol)-OH (119)

Following procedures for preparation of compound (115), and substitutingBoc-Leu-OH for Boc-Asn-OH, provided the title compound (119). MS (ESI)m/z 407.39 (M+H⁺).

Example 15 H-Lys-Asp(OPropofol)-OH (120)

Following procedures for preparation of compound (115), and substitutingα-N-Boc-ε-N-Boc-Lys-OH for Boc-Asn-OH, provided the title compound(120). MS (ESI) m/z 422.61 (M+H⁺).

Example 16 H-Met-Asp(OPropofol)-OH (121)

Following procedures for preparation of compound (115), and substitutingBoc-Met-OH for Boc-Asn-OH, provided the title compound (121). MS (ESI)m/z 425.14 (M+H⁺).

Example 17 H-Tyr-Asp(OPropofol)-OH (122)

Following procedures for preparation of compound (115), and substitutingBoc-Tyr(O^(t)Bu)-OH for Boc-Asn-OH, provided the title compound (122).MS (ESI) m/z 457.33 (M+H⁺).

Example 18 H-Ala-Glu(OPropofol)-OH (123)

Following procedures for preparation of compound (107), and substitutingcompound (105) for compound (102) provided the title compound (123).¹H-NMR (400 MHz, CD₃OD): δ 7.16 (m, 3H), 4.35 (dd, J=5.2, 7.6 Hz 1H),3.96 (q, J=7.2, 1H), 2.94–2.87 (m, 2H), 2.75 (m, 2H), 2.33 (m, 1H), 2.18(m, 1H), 1.53 (d, J=6.8 Hz 3H), 1.18 (d, J=7.2 Hz, 12H). MS (ESI) m/z379.34 (M+H⁺).

Example 19 H-Asn-Glu(OPropofol)-OH (124)

Following procedures for preparation of compound (123), and substitutingCBz-Asn-OH for CBz-Ala-OH provided the title compound (124). ¹H-NMR (400MHz, CD₃OD): δ 7.16 (m, 3H), 4.38 (dd, J=7.6, 5.2 Hz 1H), 4.23 (dd,J=9.2, 3.6 Hz, 1H), 3.00 (dd, J=16.8, 3.6 Hz, 1H), 2.91 (m, 2H), 2.77(m, 3H), 2.33 (m, 1H), 2.16 (m, 1H), 1.18 (d, J=6.8 Hz, 12H). MS (ESI)m/z 422.35 (M+H⁺). MS (ESI) m/z 422.35 (M+H⁺).

Example 20 H-Leu-Glu(OPropofol)-OH (125)

Following procedures for preparation of compound (123) and substitutingCBz-Leu-OH for CBz-Ala-OH provided the title compound (125). ¹H-NMR (400MHz, CD₃OD): δ 7.16 (m, 3H), 4.35 (t, J=7.2 Hz, 1H), 3.93 (dd, J=8.4,5.6 Hz, H), 2.91 (m, 2H), 2.75 (m, 2H), 2.32 (m, 1H), 2.15 (m, 1H),1.83–1.58 (m, 3H), 1.18 (d, J=6.8 Hz, 12H), 0.98 (m, 6H). MS (ESI) m/z421.40 (M+H⁺).

Example 21 H-Asp(OPropofol)-Val-OH (126)

To a homogeneous solution of compound (103), (874 mg, 2.2 mmol) inacetonitrile (5 mL) was added dicyclohexylcarbodiimide (550 mg, 2.7mmol). N-hydroxysuccinimide (358 mg, 3.1 mmol) was then added and thereaction was allowed to proceed for 6 h. The resulting dicyclohexylureawas filtered and to the filtrate was added H-Val-O^(t)Bu hydrochloride(499 mg, 2.2 mmol). Triethylamine (5 mL) was added and after stirringfor 6 h the solution was extracted with ethyl acetate (100 mL), washedwith 10% citric acid (2×25 mL), saturated sodium bicarbonate (2×25 mL)and brine (2×25 mL). The organic layer was dried over Na₂SO₄ and thenconcentrated in vacuo. The crude compound was purified by chromatographyon silica gel (Biotage), eluting with a gradient of hexane to 10%EtOAc/hexane) then the eluant concentrated in vacuo. The product wasthen treated with 30% TFA (24 mL) in dichloromethane (51 mL) for 45 min,concentrated in vacuo and the residue purified by preparative LC/MS toafford the title compound (126) (72 mg, 8% yield). ¹H-NMR (400 MHz,CD₃OD): 7.19 (m, 3H), 4.34 (d, J=5.2 Hz 1H), 4.28 (m, 1H), 3.54–3.34 (m,1H), 3.23–3.16 (dd, J=8.8, 18.4 Hz, 1H), 2.95 (m, 2H), 2.25 (m, 1H),1.21 (d, J=6.8 Hz, 12H), 1.04 (dd, J=6.4, 9.6 Hz, 6H). MS (ESI) m/z393.35 (M+H⁺).

Example 22 H-Asp(OPropofol)-Ile-OH (127)

L-Isoleucine-O-Trityl resin was prepared following the protocol outlinedin Example 9, substituting Fmoc-Ile for Fmoc-Asp(OPropofol)-OH. Theisoleucine-loaded resin (500 mg, loading 1.3 mmol/g) and compound (103)(1.3 mmol) was suspended in DMF (8 mL) and diisopropylethylamine (0.68mL, 3.9 mmol) and O-(1H-Benzotriazol-1-yl) N,N,N′,N′-tetramethyluroniumhexafluorophosphate (493 mg, 1.3 mmol) was added. The reaction mixturewas shaken for 12 h after which the resin was filtered and rinsed withDMF (3×15 mL), methanol (3×15 mL), and dichloromethane (3×15 mL). Theresin was then soaked in 75% TFA (11 mL) in CH₂Cl₂ (4 mL) for 6 h. Theresin was washed with CH₂Cl₂ and the combined filtrate was collected,concentrated in vacuo and purified by preparative LC/MS to afford thetitle compound (127) (32 mg, 12% yield). ¹H-NMR (400 MHz, CD₃OD): 7.18(m, 3H), 4.34 (d, J=5.2, 1H), 4.20 (dd, J=3.6, 8.8 Hz, 1H), 3.46 (dd,J=4.0, 18.4 Hz 1H), 3.19–3.12 (dd, J=8.8, 18 Hz, 1H), 2.96 (m, 2H),2.00–1.91 (m, 1H), 1.63–1.53 (m, 1H), 1.20 (m, 1H), 1.2 (d, J=6.8 Hz,12H), 0.98 (d, J=9.2 Hz, 3H), 0.95 (t, J=7.2 Hz, 3H). MS (ESI) m/z407.36 (M+H⁺).

Example 23 H-Asp(OPropofol)-Ala-OH (128)

Following procedures for the preparation of compound (127) andsubstituting Ala-O-Trityl resin for Isoleucine-O-Trityl resin providedthe title compound (128). MS (ESI) m/z 365.32 (M+H⁺).

Example 24 H-Asp(OPropofol)-Asp-OH (129)

Following procedures for the preparation of compound (127) andsubstituting Asp(O^(t)Bu)-O-Trityl resin for Isoleucine-O-Trityl resinprovided the title compound (129). MS (ESI) m/z 409.26 (M+H⁺).

Example 25 H-Asp(OPropofol)-Gln-OH (130)

Following procedures for the preparation of compound (127) andsubstituting Gln-O-Trityl resin for Isoleucine-O-Trityl resin providedthe title compound (130). MS (ESI) m/z 422.32 (M+H⁺).

Example 26 H-Asp(OPropofol)-Glu-OH (131)

Following procedures for the preparation of compound (127) andsubstituting Glu(O-^(t)Bu)-O-Trityl resin for Isoleucine-O-Trityl resinprovided the title compound (131). MS (ESI) m/z 423.28 (M+H⁺).

Example 27 H-Asp(OPropofol)-Gly-OH (132)

Following procedures for the preparation of compound (127) andsubstituting Gly-O-Trityl resin for Isoleucine-O-Trityl resin providedthe title compound (132). MS (ESI) m/z 351.30 (M+H⁺).

Example 28 H-Asp(OPropofol)-Leu-OH (133)

Following procedures for the preparation of compound (127) andsubstituting Leu-O-Trityl resin for Isoleucine-O-Trityl resin providedthe title compound (133). MS (ESI) m/z 407.36 (M+H⁺).

Example 29 H-Asp(OPropofol)-Met-OH (134)

Following procedures for the preparation of compound (127) andsubstituting Met-O-Trityl resin for Isoleucine-O-Trityl resin providedthe title compound (134). MS (ESI) m/z 425.31 (M+H⁺).

Example 30 H-Asp(OPropofol)-Phe-OH (135)

Following procedures for the preparation of compound (127) andsubstituting Phe-O-Trityl resin for Isoleucine-O-Trityl resin providedthe title compound (135). MS (ESI) m/z 441.32 (M+H⁺).

Example 31 H-Asp(OPropofol)-Pro-OH (136)

Following procedures for the preparation of compound (127) andsubstituting Pro-O-Trityl resin for Isoleucine-O-Trityl resin providedthe title compound (136). MS (ESI) m/z 391.31 (M+H⁺).

Example 32 H-Asp(OPropofol)-Ser-OH (137)

Following procedures for the preparation of compound (127) andsubstituting Ser(O^(t)Bu)—O-Trityl resin for Isoleucine-O-Trityl resinprovided the title compound (137). MS (ESI) m/z 381.29 (M+H⁺).

Example 33 H-Glu(OPropofol)-Ala-OH (138)

Alanine-O-Trityl resin was prepared following the protocol outlined inExample 9, substituting Fmoc-Ala for Fmoc-Asp(OPropofol)-OH. Thealanine-loaded resin (1.5 g, loading 0.5 mmol/g) and compound (106) (1.4mmol) was suspended in DMF (15 mL) then diisopropylethylamine (0.73 mL,4.2 mmol) and O-(1H-Benzotriazol-1-yl)N,N,N′,N′-tetramethyluroniumhexafluorophosphate (531 mg, 1.4 mmol) was added. The reaction mixturewas shaken for 12 h after which the resin was filtered and rinsed withDMF (3×15 mL), methanol (3×15 mL), and dichloromethane (3×15 mL). Theresin was then soaked in 75% TFA (11 mL) in CH₂C¹ ₂ (4 mL) for 6 h. Theresin was washed with CH₂Cl₂ and the combined filtrate was collected,concentrated in vacuo and purified by preparative LC/MS to afford thetitle compound (138) (30 mg, 10% yield). ¹H-NMR (400 MHz, CD₃OD): 7.17(m, 3H), 4.31 (q, J=2.8 Hz, 11H), 3.95 (t, J=6.4 Hz, 1H), 2.94 (m, 4H),2.29 (m, 2H), 1.43 (d, J=7.6 Hz, 3H), 1.18 (d, J=6.4 Hz, 12H). MS (ESI)m/z 379.34 (M+H⁺).

Example 34 H-Glu(OPropofol)-Arg-OH (139)

Following procedures for the preparation of compound (138) andsubstituting Arg(Mtr)-O-Trityl resin for Ala-O-Trityl resin, and in thefinal step soaking the resin in 95% TFA (14 mL) and dichloromethane (0.8mL) for 12 h, provided the title compound (139). ¹H-NMR (400 MHz,CD₃OD): 7.17 (m, 3H), 4.29 (t, J=7.2 Hz, 1H), 3.80 (t, J=6.8 Hz, 1H),3.22 (t, J=6.8, 2H), 2.89 (m, 4H), 2.26 (m, 1H), 2.18 (m, 1H), 1.89 (m,1H), 1.79 (m, 1H), 1.69 (m, 2H), 1.18 (d, J=6.8 Hz, 12H). MS (ESI) m/z464.34 (M+H⁺).

Example 35 H-Glu(OPropofol)-Asp-OH (140)

Following procedures for the preparation of compound (138) andsubstituting Asp(O^(t)Bu)—O-Trityl resin for Ala-O-Trityl resin providedthe title compound (140). ¹H-NMR (400 MHz, CD₃OD): 7.17 (m, 3H), 4.65(dd, J=7.2, 5.2 Hz, 1H), 3.97 (t, J=6.4 Hz, 1H), 2.95 (m, 5H), 2.82 (dd,J=16, 7.2 Hz, 1H), 2.30 (q, J=12 Hz, 2H), 1.19 (d, J=6.8 Hz, 12H). MS(ESI) m/z 423.31 (M+H⁺).

Example 36 H-Glu(OPropofol)-Gln-OH (141)

Following procedures for the preparation of compound (138) andsubstituting Asn-O-Trityl resin for Ala-O-Trityl resin provided thetitle compound (141). ¹H-NMR (400 MHz, CD₃OD): 7.17 (m, 3H), 4.29 (t,J=6.4 Hz, 1H), 3.94 (m, 1H), 2.92 (m, 4H), 2.29 (q, J=7.6 Hz, 4H), 2.18(m, 1H), 2.03 (m, 1H), 1.18 (d, J=6.4 Hz, 12H). MS (ESI) m/z 436.30(M+H⁺).

Example 37 H-Glu(OPropofol)-Glu-OH (142)

Following procedures for the preparation of compound (138) andsubstituting Glu(O^(t)Bu)—O-Trityl resin for Ala-O-Trityl resin providedthe title compound (142). ¹H-NMR (400 MHz, CD₃OD): 7.17 (m, 3H), 4.65(dd, J=8.4, 5.2 Hz, 1H), 4.29 (t, J=6.4 Hz, 1H), 2.93 (m, 4H), 2.40 (m,2H), 2.30 (m, 3H), 2.03 (m, 1H), 1.18 (d, J=6.4 Hz, 12H). MS (ESI) m/z437.30 (M+H⁺).

Example 38 H-Glu(OPropofol)-Gly-OH (143)

Following procedures for the preparation of compound (138) andsubstituting Gly-O-Trityl resin for Ala-O-Trityl resin provided thetitle compound (143). ¹H-NMR(400 MHz, CD₃OD): 7.17 (m, 3H), 3.97 (m,2H), 3.71 (ABq, J=108 Hz, 17.2 Hz, 1H), 2.89 (m, 4H), 2.27 (m, 2H), 1.19(d, J=6.8 Hz, 12H). MS (ESI) m/z 365.34 (M+H⁺).

Example 39 H-Glu(OPropofol)-Ile-OH (144)

Following procedures for the preparation of compound (138) andsubstituting Ile-O-Trityl resin for Ala-O-Trityl resin provided thetitle compound (144). ¹H-NMR (400 MHz, CD₃OD): 7.17 (m, 3H), 4.32 (d,J=4.8 Hz, 1H), 3.94 (t, J=6.0 Hz, 1H), 2.91 (m, 4H), 2.27 (m, 2H), 1.95(m, 1H), 1.58 (m, 1H), 1.18 (d, J=6.8 Hz, 13H), 0.97 (m, 6H). MS (ESI)m/z 421.35 (M+H⁺).

Example 40 H-Glu(OPropofol)-Leu-OH (145)

Following procedures for the preparation of compound (138) andsubstituting Leu-O-Trityl resin for Ala-O-Trityl resin provided thetitle compound (145). ¹H-NMR (400 MHz, CD₃OD): 7.17 (m, 3H), 4.38 (dd,J=10.4, 4.8 Hz, 1H), 3.91 (t, J=6.4 Hz, 1H), 2.92 (m, 4H), 2.81 (m, 2H),1.70 (m, 3H), 1.18 (d, J=6.8 Hz, 13H), 0.97 (dd, J=6.4, 4.4 Hz, 6H). MS(ESI) m/z 421.35 (M+H⁺).

Example 41 H-Glu(OPropofol)-Lys-OH (146)

Following procedures for the preparation of compound (138) andsubstituting Lys(ε—N-Boc)-O-Trityl resin for Ala-O-Trityl resin providedthe title compound (146). ¹H-NMR (400 MHz, CD₃OD): 7.17 (m, 3H), 4.65(t, J=7.2 Hz, 1H), 3.86 (t, J=6.4 Hz, 1H), 2.92 (m, 6H), 2.27 (m, 2H),1.88 (m, 1H), 1.74 (m, 3H), 1.48 (m, 2H), 1.18 (d, J=6.4 Hz, 12H). MS(ESI) m/z 436.39 (M+H⁺).

Example 42 H-Glu(OPropofol)-Met-OH (147)

Following procedures for the preparation of compound (138) andsubstituting Met-O-Trityl resin for Ala-O-Trityl resin provided thetitle compound (147). ¹H-NMR (400 MHz, CD₃OD): 7.16 (m, 3H), 4.40 (dd,J=7.6, 4.0 Hz, 1H), 3.94 (t, J=6.4 Hz, 1H), 2.92 (m, 4H), 2.56 (m, 2H),2.29 (m, 2H), 2.18 (m, 1H), 2.09 (s, 3H), 2.01 (m, 11H), 1.18 (d, J=6.4Hz, 12H). MS (ESI) m/z 439.30 (M+H⁺).

Example 43 H-Glu(OPropofol)-Phe-OH (148)

Following procedures for the preparation of compound (138) andsubstituting Phe-O-Trityl resin for Ala-O-Trityl resin provided thetitle compound (148). ¹H-NMR (400 MHz, CD₃OD): 7.26 (m, 4H), 7.17 (m,3H), 4.55 (dd, J=9.2, 4.8 Hz, 1H), 3.82 (t, J=6.0 Hz, 1H), 3.28–3.00(dd, 2H), 2.89 (m, 2H), 2.82 (m, 2H), 2.22 (m, 2H), 2.09 (s, 3H), 2.01(m, 1H), 1.18 (d, J=6.8 Hz, 12H). MS (ESI) m/z 455.35 (M+H⁺).

Example 44 H-Glu(OPropofol)-Ser-OH (149)

Following procedures for the preparation of compound (138) andsubstituting Ser(O^(t)Bu)-O-Trityl resin for Ala-O-Trityl resin providedthe title compound (149). (400 MHz, CD₃OD): 7.17 (m, 3H), 4.39 (t, J=5.6Hz, 1H), 4.00 (t, J=5.6 Hz, 1H), 3.89 (m, 2H), 2.30 (m, 2H), 1.18 (d,J=6.8 Hz, 12H). MS (ESI) m/z 395.51 (M+H⁺).

Example 45 H-Glu(OPropofol)-Val-OH (150)

Following procedures for the preparation of compound (138) andsubstituting Val-O-Trityl resin for Ala-O-Trityl resin provided thetitle compound (150). (400 MHz, CD₃OD): 7.17 (m, 3H), 4.28 (d, J=5.2 Hz,1H), 3.98 (t, J=6.4 Hz, 1H), 2.92 (m, 4H), 2.28 (m, 3H), 1.18 (d, J=6.4Hz, 12H), 1.00 (dd, J=11.6, 6.4 Hz, 6H). MS (ESI) m/z 407.52 (M+H⁺).

Example 46 H-Val-OPropofol (151)

To homogeneous solution of Boc-Valine-OH (234 mg, 1.1 mmol) in toluene(5 mL) was added DCC (333 mg, 1.6 mmol). DMAP (11 mg, 0.1 mmol) andpropofol (199 μL, 1.1 mmol) and the reaction mixture was allowed to stiruntil the solution became homogeneous. It was then placed in a 60° C.oil bath and allowed to stir for a further 8 h. The reaction mixture wasthen cooled to room temperature, the dicyclohexylurea was filtered offand the solution was diluted with ether (100 mL). The ether layer waswashed with 10% citric acid (2×25 mL), saturated sodium bicarbonate(2×25 mL), and brine (2×25 mL). The organic layer was dried over Na₂SO₄and then concentrated in vacuo. The crude compound was purified byradial chromatography on silica gel, eluting with a gradient of hexaneto 50% ethyl acetate/hexane. The resulting residue was treated with 20%TFA (4 mL) in dichloromethane (16 mL) at room temperature for 30 min.After removing the solvent, the resulting residue was purified bypreparative LC/MS to afford the title compound (151) (60 mg, 20% yield).¹H-NMR (400 MHz, CD₃OD): δ 7.24 (m, 3H), 4.46 (d, J=3.2 Hz, 1H), 2.92(m, 2H), 2.68 (m, 1H), 1.27 (d, J=7.6 Hz, 3H), 1.21–1.19 (d, J=6.8 Hz,15H). MS (ESI) m/z 278.30 (M+H⁺).

Example 47 H-Ala-OPropofol Hydrochloride (152)

Following procedures for the preparation of compound (151) andsubstituting Boc-Ala-OH for Boc-Val-OH. The hydrochloride salts wereprepared by treating the desired compound with a solution of 1 N HClaqueous solution to provide the title compound (152). ¹H-NMR (400 MHz,CD₃OD): δ 7.19–7.27 (m, 3H), 4.57 (q, J=7.2 Hz, 1H), 2.92 (m, 2H), 1.81(d, J=7.2 Hz, 3H), 1.21 (d, J=6.8 Hz, 12H). MS (ESI) m/z 252.44 (M+H⁺).

Example 48 H-Asn-OPropofol Hydrochloride (153)

Following procedures for the preparation of compound (151) andsubstituting Boc-Asn(Trt)-OH for Boc-Val-OH provided the crude product.After purification the residue was treated with 90% TFA (45 mL) indichloromethane (4.5 mL) and 1% triisopropylsilane (0.5 mL) for 4 h.After removal of the solvent the resulting residue was purified bypreparative LC/MS and treated with one molar equivalent of 1 N HClaqueous solution to afford the title compound (153). ¹H-NMR (400 MHz,CD₃OD): δ 7.23–7.19 (m, 3H), 4.73–4.71 (m, 1H), 3.23–3.17 (m, 2H), 2.94(m, 2H), 1.19 (d, J=6.4 Hz, 12H). MS (ESI) m/z 294.34 (M+H⁺).

Example 49 H-His-OPropofol (154)

Following procedures for the preparation of compound (151) andsubstituting Boc-His(Boc)-OH for Boc-Val-OH provided the title compound(154). ¹H-NMR (400 MHz, CD₃OD): δ 8.98 (s, 1H), 7.64 (s, 1H), 7.28–7.20(m, 3H), 5.02–4.99 (dd, J=9.6, 5.6 Hz, 1H), 3.86–3.81 (m, 1H), 3.59–3.53(dd, J=16.0, 9.6 Hz, 1H), 2.95 (m, 1H), 2.78 (m, 1H), 1.19 (d, J=6.4 Hz,12H). MS (ESI) m/z 317.33 (M+H⁺)

Example 50 H-Lys-OPropofol Hydrochloride (155)

Following procedures for the preparation of compound (151) andsubstituting α-N-Boc-Lys(ε-N-Boc)-OH for Boc-Val-OH. After LC/MSpurification, the residue was treated with two molar equivalent of 1 NHCl aqueous solution to provide the title compound (155). ¹H-NMR (400MHz, CD₃OD): δ 7.20–7.28 (m, 3H), 4.52 (t, J=6.0 Hz, 1H), 3.01–2.89 (m,4H), 2.35–2.29 (m, 1H), 2.16–2.09 (m, 1H), 1.81–1.67 (m, 4H), 1.21–1.20(d, J=6.8 Hz, 12H). MS (ESI) m/z 307.36 (M+H⁺).

Example 51 H-Met-OPropofol (156)

Following procedures for the preparation of compound (151) andsubstituting Boc-Met-OH for Boc-Val-OH provided the title compound(156). MS (ESI) m/z 310.22 (M+H⁺).

Example 52 H-Phe-OPropofol (157)

Following procedures for the preparation of compound (151) andsubstituting Boc-Phe-OH for Boc-Val-OH provided the title compound(157). ¹H-NMR (400 MHz, CD₃OD): δ 7.43–7.33 (m, 5H), 7.21 (m, 3H), 4.74(dd, J=8.8, 6.0 Hz, 1H), 3.62 (dd, J=14, 6.0 Hz, 1H), 3.22 (dd, J=14.4,9.2 Hz, 1H), 2.86 (m, 2H), 1.18 (d, J=6.8 Hz, 12H). MS (ESI) m/z 326.25(M+H⁺). MS (ESI) m/z 326.25 (M+H⁺).

Example 53 H-Ser-OPropofol (158)

Following procedures for the preparation of compound (151) andsubstituting Boc-Ser(O^(t)Bu)-OH for Boc-Val-OH provided the titlecompound (158). ¹H-NMR (400 MHz, CD₃OD): δ 7.21–7.17 (m, 3H), 4.39 (t,J=2.8 Hz, 1H), 4.16–3.84 (ABq, J=10, 3.2 Hz, 2H), 1.19 (d, J=7.2 Hz,12H). MS (ESI) m/z 266.33 (M+H⁺).

Example 54 H-Asp(OPropofol)-OH (159)

To a flask containing 500 mg of 10% Pd—C was added a solution ofcompound (102) in methanol under nitrogen. The resulting mixture wasdegassed three times, after which hydrogen was introduced via a balloonapparatus. The suspended mixture was allowed to stir vigorously for 4 h.The reaction mixture was filtered through a pad of celite andconcentrated in vacuo to arrive at the title compound (159). MS (ESI)m/z 294.36 (M+H⁺).

Example 55 H-Glu(OPropofol)-OH (160)

To a flask containing 500 mg of 10% Pd—C was added a solution ofcompound (105) in methanol under nitrogen. The resulting mixture wasdegassed three times, after which hydrogen was introduced via a balloonapparatus. The suspended mixture was allowed to stir vigorously for 4 h.The reaction mixture was filtered through a pad of celite andconcentrated in vacuo to arrive at the title compound (160). MS (ESI)m/z 308.39 (M+H⁺).

Example 56 H-Ala-Ser(β-OC(O)OPropofol)-OH (161) Step A:Boc-Ala-Ser-O^(t)Bu (162)

To a solution of L-Boc-alanine (567 mg, 3 mmol) and L-serine α-t-butylester in DMF (6 mL) was added diisopropylethylamine (1 mL, 6.2 mmol)followed by O-(7-azabenzotriazol-1-yl)-N,N, N′,N′-tetramethyluroniumhexafluoro-phosphate (591 mg, 3 mmol). The resulting mixture was stirredat room temperature for 14 h and then diluted with 40 mL of ethylacetate. The organic solution was washed with 10% aqueous citric acidsolution (2×30 mL), saturated aqueous sodium bicarbonate solution (2×30mL) and brine (2×30 mL). The organic layer was dried over magnesiumsulfate and then concentrated in vacuo. The crude compound (162) wasused without further purification.

Step B: 2,6-Bis(isopropyl)phenoxycarbonyl chloride (163)

Phosgene (13 mL, 20% in toluene) was added to propofol (3.6 g, 20 mmol)under a nitrogen atmosphere. The mixture was cooled to 0° C. andN,N-dimethylaniline (3.3 mL, 26 mmol) was added dropwise. The reactionmixture was allowed to warm to room temperature slowly and stirred for14 h. The solvent was removed in vacuo. The crude product was carried tonext step without further purification.

Step C: Boc-Ala-Ser(β-OC(O)OPropofol)-O^(t)Bu (164)

To an ice cold solution of chloroformate (163) (720 mg, 3 mmol) indichloromethane (10 mL) was added triethylamine (0.35 mL, 6 mmol)followed by compound (162). The resulting mixture was allowed to warm toroom temperature and stirred for 12 h. The mixture was diluted withethyl acetate (30 mL) and washed with 10% aqueous citric acid solution(2×30 mL), dried over MgSO₄, filtered and concentrated in vacuo. Thecrude product (164) was used in the next step without purification.

Step D: H-Ala-Ser(β-OC(O)OPropofol)-OH (161)

The crude compound (164) from above was dissolved in dichloromethane (2mL) and treated with trifluoroacetic acid (1 mL). The resulting mixturewas stirred at room temperature for 3 h. The solvent was removed invacuo and the crude residue was purified by reverse phase LC/MS toafford 25 mg of the title compound (161). ¹H-NMR (400 MHz, CD₃OD): δ7.12–7.20 (m, 3H), 4.59 (br. s, 3H), 3.99 (q, J=7.2 Hz, 2H), 2.99 (m,2H), 1.56 (d, J=6.8 Hz, 3H), 1.18 (d, J=7.2 Hz, 12H). MS (ESI) m/z381.31 (M+H⁺).

Example 57 H-Tyr-OPropofol Hydrochloride (165)

Following procedures for the preparation of compound (151) andsubstituting Boc-Tyr-OH for Boc-Val-OH; after LC/MS purification, theresidue was treated with one molar equivalent of 1 N HCl aqueoussolution to provide the title compound (165). ¹H-NMR (400 MHz, CD₃OD): δ7.26–7.18 (m, 5H), 6.83–6.81 (dd, J=9.2, 2.8 Hz, 2H), 4.75–4.71 (dd,J=9.2, 5.2 Hz, 1H), 3.59–3.54 (dd, J=14.4, 5.6 Hz, 1H), 3.16–3.10 (dd,J=14.4, 9.2 Hz, 1H), 2.85 (m, 2H), 1.18 (d, J=6.8 Hz, 12H). MS (ESI) m/z343.43 (M+H⁺).

Example 58 H-Gln-OPropofol Hydrochloride (166)

Following procedures for the preparation of compound (151) andsubstituting Boc-Tyr-OH for Boc-Gln(tBu)-OH; after LC/MS purification,the residue was treated with one molar equivalent of 1 N HCl aqueoussolution to provide the title compound (166). ¹H-NMR (400 MHz, CD₃OD): δ7.26–7.19 (m, 3H), 4.58–4.55 (dd, J=7.6, 5.2 Hz, 1H), 2.89 (s, 2H), 2.68(m, 2H), 2.56–2.52 (m, 2H), 2.32–2.27 (m, 2H), 1.21 (t, J=6.8 Hz, 12H).MS (ESI) m/z 308.34 (M+H⁺).

Example 59 H-Gly-OPropofol Hydrochloride (167)

Following procedures for the preparation of compound (151) andsubstituting Boc-Tyr-OH for Boc-Gly-OH; after LC/MS purification, theresidue was treated with one molar equivalent of 1 N HCl aqueoussolution to provide the title compound (167). ¹H-NMR (400 MHz, CD₃OD): δ7.25–7.19 (m, 3H), 4.27 (s, 2H), 2.95–2.92 (m, 2H), 1.19 (d, J=6.8 Hz,12H). MS (ESI) m/z 237.33 (M+H⁺).

Example 60 H-Thr-OPropofol Hydrochloride (168)

Following procedures for the preparation of compound (151) andsubstituting Boc-Tyr-OH for Boc-Thr(O^(t)Bu)-OH; after LC/MSpurification, the residue was treated with one molar equivalent of 1 NHCl aqueous solution to provide the title compound (168). ¹H-NMR (400MHz, CD₃OD): δ 7.25–7.19 (m, 3H), 4.71–4.69 (dd, J=7.6, 5.2 Hz, 1H),4.44 (d, J=2.8 Hz, 1H), 3.14 (m, 1H), 2.94 (m, 1H), 1.46 (d, J=6.8 Hz,3H), 1.19 (d, J=6.8 Hz, 12H). MS (ESI) m/z 281.48 (M+H⁺).

Example 61 H-Pro-OPropofol Hydrochloride (169)

Following procedures for the preparation of compound (151) andsubstituting Boc-Tyr-OH for Boc-Pro-OH; after LC/MS purification, theresidue was treated with one molar equivalent of 1 N HCl aqueoussolution to provide the title compound (169). ¹H-NMR (400 MHz, CD₃OD): δ7.28–7.21 (m, 3H), 4.85 (m, 1H), 3.52–3.39 (m, 2H), 2.91 (m, 2H),2.73–2.70 (m, 1H), 2.39–2.34 (m, 1H), 2.26–2.16 (m, 2H), 1.21 (t, J=6.8Hz, 12H). MS (ESI) m/z 277.42 (M+H⁺).

Example 62 H-Val-Asn-OPropofol (170)

A solution of Boc-Val-OH (0.28 g, 1.28 mmol) in 4 mL of DMF was treatedwith O-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (0.5 g, 1.31 mmol) followed by diisopropylethylamine(0.5 mL, 2.9 mmol). The reaction mixture was stirred for 5 min, and thena solution of (153) in DMF (1 mL) was added. The resulting mixture wasstirred at room temperature for 14 h. The mixture was then diluted with10% aqueous citric acid solution (15 mL) and ethyl acetate (30 mL). Thelayers were separated and the organic layer was washed with saturatedNaHCO₃ aqueous solution (15 mL) and brine (2×15 mL), dried over MgSO₄and concentrated in vacuo. The crude product was purified bychromatography on silica gel (Biotage), eluting with a gradient ofhexane to 60% ethyl acetate/hexane. The solvent was removed in vacuo,the residue dissolved in anhydrous dichloromethane (5 mL) and treatedwith trifluoroacetic acid (1 mL). The mixture was stirred at roomtemperature for 2 h, concentrated in vacuo and purified by preparativeLC/MS to afford the title compound (170) (267 mg, 53% yield). ¹H-NMR(400 MHz, CD₃OD): δ 7.22–7.14 (m, 3H), 5.16 (t, J=6.4 Hz, 1H), 3.58 (s,1H), 3.03–2.96 (m, 4H), 2.14 (s, 1H), 1.17 (t, J=6.8 Hz, 12H), 1.04 (d,J=6.8 Hz, 3H), 1.00 (d, J=6.8 Hz, 3H). MS (ESI) m/z 408.37 (M+H⁺).

Example 63 H-Gly-Asn-OPropofol (171)

Following procedures for preparation of H-Val-Asn-OPropofol, andsubstituting Boc-Val-OH with Boc-Gly-OH, provided the title compound(171). ¹H-NMR (400 MHz, CD₃OD): δ 7.09–7.11(m, 3H), 5.21 (m, 1H), 3.672(m, 2H), 2.96–3.04 (m, 4H), 1.18 (d, J=7.2 Hz, 12H). MS (ESI) m/z350.3(M+H⁺).

Example 64 H-Ala-Asn-OPropofol (172)

Following procedures for preparation of H-Val-Asn-OPropofol, andsubstituting Boc-Val-OH with Boc-Ala-OH, provided the title compound(172). ¹H-NMR (400 MHz, CD₃OD): δ 7.09–7.11(m, 3H), 5.21 (m, 1H), 3.98(m, 1H), 2.96–3.04 (m, 4H), 1.48–1.5 (d, J=9.8 Hz, 3H), 1.18 (d, J=7.2Hz, 12H). MS (ESI) m/z 364.5(M+H⁺).

Example 65 H-Gln-Asn-OPropofol (173)

Following procedures for preparation of H-Val-Asn-OPropofol, andsubstituting Boc-Val-OH with Boc-Gln-OH, provided the title compound(173). ¹H-NMR (400 MHz, CD₃OD): δ 7.14–7.21(m, 3H), 5.16–5.19 (m, 1H),3.86–3.95 (m, 1H), 2.95–3.00 (m, 4H), 2.5 (m, 2H), 2.14(m, 2H), 1.18 (d,J=7.2 Hz, 12H). MS (ESI) m/z 421.3 (M+H⁺).

Example 66 H-Ser-Asn-OPropofol (174)

Following procedures for preparation of H-Val-Asn-OPropofol, andsubstituting Boc-Val-OH with Boc-Ser-OH, provided the title compound(174). ¹H-NMR (400 MHz, CD₃OD): δ 7.14–7.21 (m, 3H), 5.16–5.19 (m, 1H),3.9–3.94(m, 2H), 3.86–3.89 (m, 1H), 2.95–3.00 (m, 4H), 1.18 (d, J=7.2Hz, 12H). MS (ESI) m/z 380.3 (M+H⁺).

Example 67 H-Dap-Asn-OPropofol (175)

Following procedures for preparation of H-Val-Asn-OPropofol, andsubstituting Boc-Val-OH with Boc-Dap(Boc)-OH, provided the titlecompound (175). ¹H-NMR (400 MHz, CD₃OD): δ 7.20–7.14 (m, 3H), 5.16–5.12(m, 1H), 3.73 (t, J=8.0 Hz, 1H), 3.27–3.23 (m, 1H), 3.08–2.94 (m, 5H),1.18–1.14 (t, J=6.8 Hz, 12H). MS (ESI) m/z 379.39 (M+H⁺).

Example 68 H-Asp-Asn-OPropofol (176)

Following procedures for preparation of H-Val-Asn-OPropofol, andsubstituting Boc-Val-OH with Boc-Asp(O^(t)Bu)-OH, provided the titlecompound (176). ¹H-NMR (400 MHz, CD₃OD): δ 7.19–7.14 (m, 3H), 5.19 (dd,J=8, 4.8 Hz, 1H), 4.14 (dd, J=9.6, 4 Hz, 1H), 3.04–2.89 (m, 4H),2.81–2.75 (dd, J=16.8, 2.4 Hz, 1H), 2.59–2.52 (dd, J=14.4, 8.4 Hz, 1H),1.18 (d, J=6.8 Hz, 6H), 1.16 (d, J=6.8 Hz, 6H). MS (ESI) m/z 408.37(M+H⁺).

Example 69 H-Tyr-Asn-OPropofol (177)

Following procedures for preparation of H-Val-Asn-OPropofol, andsubstituting Boc-Val-OH with Boc-Tyr-OH, provided the title compound(177). ¹H-NMR (400 MHz, CD₃OD): δ 7.22–7.15 (m, 3H), 7.10–7.08 (d, J=8.4Hz, 2H), 6.70 (d, J=8.4 Hz, 2H), 5.18 (t, J=6.0 Hz, 1H), 3.97–3.94 (dd,J=8.4, 5.2 Hz, 1H), 3.18–3.13 (dd, J=14.4, 5.2 Hz, 1H), 3.03–2.98 (m,4H), 2.88–2.82 (dd, J=16.8, 10 Hz, 1H), 1.18–1.15 (t, J=6.8 Hz, 12H). MS(ESI) m/z 456.64 (M+H⁺).

Example 70 H-Asp-Ala-OPropofol (178)

Following procedures for preparation of H-Val-Asn-OPropofol,substituting Boc-Val-OH with Boc-Asp(O^(t)Bu)-OH and compound (153) with(152), provided the title compound (178). ¹H-NMR (400 MHz, CD₃OD): δ7.22–7.14 (m, 3H), 4.80–4.75 (q, J=7.2 Hz, 1H), 4.15–4.12 (m, 1H),2.97–2.91 (m, 2H), 2.82–2.76 (dd, J=16.4, 3.6 Hz, 1H), 2.58–2.51 (dd,J=17.2, 10.4 Hz, 1H), 1.64 (d, J=7.6 Hz, 3H), 1.18 (d, J=6.4 Hz, 12H).MS (ESI) m/z 365.17 (M+H⁺).

Example 71 H-Val-Ala-OPropofol (179)

Following procedures for preparation of H-Val-Asn-OPropofol,substituting compound (153) with (152), provided the title compound(179). ¹H-NMR (400 MHz, CD₃OD): δ 7.22–7.14 (m, 3H), 4.83–4.78 (q, J=7.2Hz, 1H), 3.66 (d, J=5.6 Hz, 1H), 3.04–2.94 (m, 2H), 2.22–2.18 (m, 1H),1.64 (d, J=7.2 Hz, 3H), 1.17 (d, J=6.4 Hz, 12H), 1.08 (d, J=6.8 Hz, 3H),1.05 (d, J=7.2 Hz, 3H). MS (ESI) m/z 349.18 (M+H⁺).

Example 72 H-Dap-Ala-OPropofol (180)

Following procedures for preparation of H-Val-Asn-OPropofol,substituting Boc-Val-OH with Boc-Dap(Boc)-OH and compound (153) with(152), provided the title compound (180). ¹H-NMR (400 MHz, CD₃OD): δ7.22–7.14 (m, 3H), 4.80–4.75 (q, J=7.6 Hz, 1H), 3.81–3.77 (dd, J=8.4,5.2 Hz, 1H), 3.27–3.22 (dd, J=13.2, 5.2 Hz, 1H), 3.05–3.00 (dd, J=13.2,8.4 Hz, 1H), 3.02–2.91 (m, 2H), 1.67 (d, J=7.6 Hz, 3H), 1.18 (d, J=6.8Hz, 12H). MS (ESI) m/z 336.30 (M+H⁺).

Example 73 H-Asp-Ser-OPropofol (181)

Following procedures for preparation of H-Val-Asn-OPropofol,substituting Boc-Val-OH with Boc-Asp(O^(t)Bu)-OH and compound (153) with(158), provided the title compound (181). ¹H-NMR (400 MHz, CD₃OD): δ7.21–7.14 (m, 3H), 4.82–4.77 (m, 1H), 4.27–4.24 (dd, J=8.8, 4.0 Hz, 1H),4.19–4.15 (dd, J=10.4, 4.8 Hz, 1H), 4.03–3.99 (dd, J=11.2, 4.0 Hz, 1H),3.04–2.94 (m, 2H), 2.97–2.91 (dd, J=17.6, 4.8 Hz, 1H), 2.79–2.73 (dd,J=17.6, 9.2 Hz, 1H), 1.17 (m, 12H). MS (ESI) m/z 381.4 (M+H⁺).

Example 74 H-Val-Ser-OPropofol (182)

Following procedures for preparation of H-Val-Asn-OPropofol,substituting compound (153) with (158), provided the title compound(182) as the formate salt. ¹H-NMR (400 MHz, CD₃OD): δ 8.48 (s, 1H),7.29–7.14 (m, 3H), 4.48 (m, 1H), 4.14–4.11 (m, 1H), 4.04–4.00 (m, 1H),3.64 (t, J=5.2 Hz, 1H), 3.05–3.02 (m, 2H), 2.21 (m, 1H), 1.17 (m, 12H),1.05 (m, 6H). MS (ESI) m/z 365.34 (M+H⁺).

Example 75 H-Ala-Tyr-OPropofol (183)

Following procedures for preparation of H-Val-Asn-OPropofol,substituting Boc-Val-OH with Boc-Ala-OH and compound (153) with (165),provided the title compound (183). ¹H-NMR (400 MHz, CD₃OD): δ 7.20–7.12(m, 5H), 6.73 (d, J=7.6 Hz, 2H), 5.05–5.01 (dd, J=8.8, 6.4 Hz, 1H), 3.64(m, 1H), 3.29–3.24 (m, 1H), 3.04–2.98 (dd, J=13.6, 9.2 Hz, 1H), 2.90 (m,1H), 2.61 (m, 1H), 1.37 (d, J=6.8 Hz, 3H), 1.12 (m, 12H). MS (ESI) m/z413.45 (M+H⁺).

Example 76 H-Glu-Tyr-OPropofol (184)

Following procedures for preparation of H-Val-Asn-OPropofol,substituting Boc-Val-OH with Boc-Glu(O^(t)Bu)-OH and compound (153) with(165), provided the title compound (184). ¹H-NMR (400 MHz, CD₃OD): δ7.20–7.13 (m, 5H), 6.73 (d, J=8.0 Hz, 2H), 5.05–5.01 (dd, J=9.6, 6.0 Hz,1H), 3.85–3.82 (dd, J=8.0, 4.4 Hz, 1H), 3.36–3.32 (m, 1H), 3.05–2.99(dd, J=14.0, 9.6 Hz, 1H), 2.94 (m, 1H), 2.63 (m, 1H), 2.51–2.41 (m, 2H),2.11–1.96 (m, 2H), 1.12 (m, 12H). MS (ESI) m/z 471.43 (M+H⁺).

Example 77 H-Dap-Tyr-OPropofol (185)

Following procedures for preparation of H-Val-Asn-OPropofol,substituting Boc-Val-OH with Boc-Dap(Boc)-OH and compound (153) with(165), provided the title compound (185) as the formate salt. ¹H-NMR(400 MHz, CD₃OD): δ 8.45 (s, 1H), 7.21–7.13 (m, 5H), 6.74 (d, J=8.4 Hz,2H), 5.04–5.01 (dd, J=9.6, 6.0 Hz, 1H), 3.58–3.55 (dd, J=8.8, 5.2 Hz,1H), 3.38–3.35 (m, 1H), 3.13–3.04 (m, 2H), 2.93 (m, 1H), 2.87–2.82 (dd,J=12.4, 8.4 Hz, 1H), 2.70 (m, 1H), 1.14 (m, 12H). MS (ESI) m/z 428.42(M+H⁺).

Example 78 H-Ser-Tyr-OPropofol (186)

Following procedures for preparation of H-Val-Asn-OPropofol,substituting Boc-Val-OH with Boc-Ser-OH and compound (153) with (165),provided the title compound (186). ¹H-NMR (400 MHz, CD₃OD): δ 7.21–7.13(m, 5H), 6.74 (d, J=8.4 Hz, 2H), 5.08–5.04 (dd, J=8.8, 6.8 Hz, 1H),3.88–3.85 (dd, J=10.8, 4.0 Hz, 1H), 3.75–3.63 (m, 2H), 3.31–3.27 (m,1H), 3.06–3.00 (dd, J=14.0, 9.2 Hz, 1H), 2.89 (m, 1H), 2.58 (m, 1H),1.14 (m, 12H). MS (ESI) m/z 429.44 (M+H⁺).

Example 79 H-Pro-Tyr-OPropofol (187)

Following procedures for preparation of H-Val-Asn-OPropofol,substituting Boc-Val-OH with Boc-Pro-OH and compound (153) with (165),provided the title compound (187). ¹H-NMR (400 MHz, CD₃OD): δ 7.21–7.13(m, 5H), 6.74 (d, J=8.4 Hz, 2H), 5.05–5.02 (dd, J=9.6, 6.0 Hz, 1H),4.08–4.05 (dd, J=8.4, 4.8 Hz, 1H), 3.37–3.35 (m, 1H), 3.29–3.13 (m, 2H),3.06–3.00 (dd, J=14.0, 9.6 Hz, 1H), 2.93 (m, 1H), 2.66 (m, 1H), 2.34 (m,1H), 1.97–1.87 (m, 3H), 1.13 (m, 12H). MS (ESI) m/z 439.42 (M+H⁺).

Example 80 H-Val-Tyr-OPropofol (188)

Following procedures for preparation of H-Val-Asn-OPropofol,substituting compound (153) with (165), provided the title compound(188) as the trifluoroacetate salt. ¹H-NMR (400 MHz, CD₃OD): δ 7.18–7.13(m, 5H), 6.74 (d, J=8.8 Hz, 2H), 5.11–5.07 (dd, J=9.6, 6.0 Hz, 1H), 3.67(d, J=4.8 Hz, 1H), 3.37–3.32 (dd, J=14.0, 5.6 Hz, 1H), 3.06–3.00 (dd,J=14.0, 9.2 Hz, 1H), 2.93 (m, 1H), 2.66 (m, 1H), 2.24 (m, 1H), 1.09 (m,15H), 1.02 (d, J=6.8 Hz, 3H). MS (ESI) m/z 442.39 (M+H⁺).

Example 81 H-Asn-Tyr-OPropofol (189)

Following procedures for preparation of H-Val-Asn-OPropofol,substituting Boc-Val-OH with Boc-Asn-OH and compound (153) with (165),provided the title compound (189) as the trifluoroacetate salt. ¹H-NMR(400 MHz, CD₃OD): δ 7.19–7.13 (m, 5H), 6.74 (d, J=8.0 Hz, 2H), 5.04–5.00(dd, J=10.4, 5.6 Hz, 1H), 4.17–4.14 (dd, J=10.0, 4.0 Hz, 1H), 3.41–3.37(dd, J=14.0, 5.2 Hz, 1H), 3.03–2.87 (m, 3H), 2.72–2.65 (m, 2H), 1.14 (m,12H). MS (ESI) m/z 457.36 (M+H⁺).

Example 82 H-Lys-Tyr-OPropofol (190)

Following procedures for preparation of H-Val-Asn-OPropofol,substituting Boc-Val-OH with Boc-Lys(Boc)-OH and compound (153) with(165), provided the title compound (190) as the trifluoroacetate salt.¹H-NMR (400 MHz, CD₃OD): δ 7.22–7.14 (m, 5H), 6.74 (d, J=8.8 Hz, 2H),5.08–5.04 (dd, J=10.4, 5.2 Hz, 1H), 3.88–3.85 (dd, J=6.0, 4.8 Hz, 1H),3.43–3.38 (dd, J=14.4, 5.2 Hz, 1H), 3.06–3.00 (dd, J=14.0, 10.0 Hz, 1H),3.06–3.00 (m, 1H), 2.84–2.79 (t, J=7.6 Hz, 2H), 2.71 (m, 1H), 1.91–1.85(q, J=8.0 Hz, 2H), 1.66–1.44 (m, 4H), 1.14 (d, J=7.2 Hz, 12H). MS (ESI)m/z 472.38 (M+H⁺).

Example 83 H-Asp-Tyr-OPropofol (191)

Following procedures for preparation of H-Val-Asn-OPropofol,substituting Boc-Val-OH with Boc-Asp(^(t)OBu)-OH and compound (153) with(165), provided the title compound (191) as the trifluoroacetate salt.¹H-NMR (400 MHz, CD₃OD): δ 7.20–7.13 (m, 5H), 6.74 (d, J=8.4 Hz, 2H),5.03–4.99 (dd, J=9.6, 6.0 Hz, 1H), 4.07–4.03 (dd, J=10.0, 4.0 Hz, 1H),3.35–3.30 (dd, J=13.6, 5.6 Hz, 1H), 3.03–2.97 (dd, J=14.0, 10.0 Hz, 1H),2.92 (m, 1H), 2.80–2.75 (dd, J=16.8, 4.0 Hz, 1H), 2.63 (m, 1H),2.56–2.49 (dd, J=17.2, 10.0 Hz, 1H), 1.12 (s, 12H). MS (ESI) m/z 458.31(M+H⁺).

Example 84 H-Gly-Tyr-OPropofol (192)

Following procedures for preparation of H-Val-Asn-OPropofol,substituting Boc-Val-OH with Boc-Gly-OH and compound (153) with (165),provided the title compound (192) as the trifluoroacetate salt. ¹H-NMR(400 MHz, CD₃OD): δ 7.21–7.13 (m, 5H), 6.74 (d, J=8.4 Hz, 2H), 5.08–5.04(dd, J=9.6, 5.6 Hz, 1H), 3.64 (dd, J=23.2, 16.0 Hz, 2H), 3.38–3.34 (dd,J=14.0, 5.6 Hz, 1H), 3.03–2.97 (dd, J=14.0, 9.6 Hz, 1H), 2.92 (m, 1H),2.68 (m, 1H), 1.13 (m, 12H). MS (ESI) m/z 400.34 (M+H⁺).

Example 85 H-Ala-Phe-OPropofol (193)

To a solution of (157) (332 mg, 1.0 mmol) and Boc-L-alanine (231 mg, 1.2mmol) in DMF (4 mL) was added diisopropylethylamine (532 μL, 3.0 mmol)followed by O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluoro-phosphate (465 mg, 1.2 mmol). The resulting mixture wasstirred at room temperature for 12 h and then diluted with 20 mL ofethyl acetate. The organic solution was washed with 10% aqueous citricacid solution (2×20 mL), saturated aqueous sodium bicarbonate solution(2×20 mL) and brine (2×20 mL). The organic layer was dried overmagnesium sulfate and then concentrated in vacuo. The resulting residuewas treated with 20% TFA (8 mL) in dichloromethane (32 mL) at roomtemperature for 30 min. After removing the solvent, the resultingresidue was purified by preparative LC/MS to afford the title compound(193) (100 mg, 25% yield). ¹H-NMR (400 MHz, CD₃OD): δ 7.37–7.15 (m, 8H),5.13 (dd, J=9.6, 5.6 Hz, 1H), 3.80 (m, 1H), 3.46 (dd, J=14.0, 6.0 Hz,1H), 3.15 (dd, J=16.8, 7.6 Hz, 1H), 1.46 (dd, J=7.2, 2.8 Hz, 1H), 1.13(m, 12H). MS (ESI) m/z 397.37 (M+H⁺).

Example 86 H-Arg-Phe-OPropofol (194)

Following procedures for the preparation of compound H-Ala-Phe-OPropofoland substituting Boc-Ala-OH with Tris-Boc-L-arginine provided the titlecompound (194). ¹H-NMR (400 MHz, CD₃OD): δ 7.38–7.15 (m, 8H), 5.13 (dd,J=10.0, 4.8 Hz, 1H), 3.89 (t, J=6.4 Hz, 1H), 3.53 (dd, J=14.4, 4.8 Hz,1H), 3.16 (m, 2H), 3.07–2.74 (m, 2H), 1.91 (m, 2H), 1.70 (m, 2H),1.23–1.10 (m, 12H). MS (ESI) m/z 482.6 (M+H⁺).

Example 87 H-Asp-Phe-OPropofol (195)

Following procedures for the preparation of compound H-Ala-Phe-OPropofoland substituting Boc-Ala-OH with Boc-Asp(O^(t)Bu)-OH provided the titlecompound (195). ¹H-NMR (400 MHz, CD₃OD): δ 7.36–7.13 (m, 8H), 5.07 (dd,J=10, 5.6 Hz, 1H), 3.89 (dd, J=9.6, 3.6 Hz, 1H), 3.45 (dd, J=14.0, 5.2Hz, 1H), 3.10 (dd, J=14.0, 10 Hz, 1H), 2.93 (m, 1H), 2.75 (m, 2H), 2.50(dd, J=17.2, 10.4 Hz, 1H), 1.23–1.03 (m, 12H). MS (ESI) m/z 441.3(M+H⁺).

Example 88 H-Gln-Phe-OPropofol (196)

Following procedures for the preparation of compound H-Ala-Phe-OPropofoland substituting Boc-Ala-OH with Boc-Gln-OH provided the title compound(196). ¹H-NMR (400 MHz, CD₃OD): δ 7.38–7.15 (m, 8H), 5.11 (dd, J=10.0,5.6 Hz, 1H), 3.89 (t, J=6.0 Hz, 1H), 3.49 (dd, J=14.0, 4.8 Hz, 1H), 3.14(dd, J=14.0, 10.0 Hz, 1H), 2.98 (m, 1H), 2.71 (m, 1H), 2.46 (t, J=7.2Hz, 2H), 2.08 (m, 2H), 1.13 (m, 12H). MS (ESI) m/z 454.3 (M+H⁺).

Example 89 H-Glu-Phe-OPropofol (197)

Following procedures for the preparation of compound H-Ala-Phe-OPropofoland substituting Boc-Ala-OH with Boc-Glu(O^(t)Bu)-OH provided the titlecompound (197). ¹H-NMR (400 MHz, CD₃OD): δ 7.37–7.14 (m, 8H), 5.10 (dd,J=10.0, 5.6 Hz, 1H), 3.83 (dd, J=8.0, 4.8 Hz, 1H), 3.47 (dd, J=14.0, 5.6Hz, 1H), 3.13 (dd, J=14.0, 10.0 Hz, 1H), 2.95 (m, 1H), 2.69 (m, 1H),2.43 (m, 2H), 2.08 (m, 2H), 1.13 (m, 12H). MS (ESI) m/z 455.7 (M+H⁺).

Example 90 H-Gly-Phe-OPropofol (198)

Following procedures for the preparation of compound H-Ala-Phe-OPropofoland substituting Boc-Ala-OH with Boc-Gly-OH provided the title compound(198). ¹H-NMR (400 MHz, CD₃OD): δ 7.36–7.15 (m, 8H), 5.14 (dd, J=10.0,5.6 Hz, 1H), 3.64 (ABq, J=28.4, 16.0 Hz, 2H), 3.45 (dd, J=14.0, 4.0 Hz,1H), 3.10 (dd, J=14.0, 10.0 Hz, 1H), 2.96 (m, 1H), 2.75 (m, 1H), 1.14(d, J=6.8 Hz, 12H). MS (ESI) m/z 383.3 (M+H⁺).

Example 91 H-His-Phe-OPropofol (199)

Following procedures for the preparation of compound H-Ala-Phe-OPropofoland substituting Boc-Ala-OH with Boc-His(Boc)-OH provided the titlecompound (199). ¹H-NMR (400 MHz, CD₃OD): δ 8.09 (s, 1H), 8.06(s, 1H),7.38–7.11 (m, 8H), 5.13 (m, 1H), 4.12 (m, 1H), 3.52 (dd, J=14.4, 5.2 Hz,1H), 3.27–3.06 (m, 2H), 2.98–2.76 (m, 2H), 2.96 (m, 1H), 1.14 (m,J=12H). MS (ESI) m/z 463.3 (M+H⁺).

Example 92 H-Pro-Phe-OPropofol (200)

Following procedures for the preparation of compound H-Ala-Phe-OPropofoland substituting Boc-Ala-OH with Boc-Pro-OH provided the title compound(200). ¹H-NMR (400 MHz, CD₃OD): δ 7.38–7.14 (m, 8H), 5.12 (dd, J=10.4,5.6 Hz, 1H), 4.19 (dd, J=14.4, 5.2 Hz, 1H), 3.13 (dd, J=14.0, 10.0 Hz,1H), 2.96 (m, 1H), 2.72 (m, 1H), 1.13 (m, J=12H). MS (ESI) m/z 424.6(M+H⁺).

Example 93 H-Ser-Phe-OPropofol (201)

Following procedures for the preparation of compound H-Ala-Phe-OPropofoland substituting Boc-Ala-OH with Boc-Ser-OH provided the title compound(201). ¹H-NMR (400 MHz, CD₃OD): δ 7.36–7.14 (m, 8H), 5.14 (dd, J=9.6,6.4 Hz, 1H), 3.95 (dd, J=10.8, 4.4 Hz, 1H), 3.70 (dd, J=11.2, 8.0 Hz,1H), 3.43 (dd, J=13.6, 5.6 Hz, 1H), 3.14 (dd, J=14, 9.6 Hz, 1H), 2.92(m, 1H), 2.64 (m, 1H), 1.12 (m, 12H). MS (ESI) m/z 413.3 (M+H⁺).

Example 94 H-Thr-Phe-OPropofol (202)

Following procedures for the preparation of compound H-Ala-Phe-OPropofoland substituting Boc-Ala-OH with Boc-Thr-OH provided the title compound(202). ¹H-NMR (400 MHz, CD₃OD): δ 7.38–7.13 (m, 8H), 5.14 (dd, J=8.8,5.6 Hz, 1H), 3.92 (m, 1H), 3.53 (d, J=7.2 Hz, 1H), 3.45 (dd, J=14.0, 5.2Hz, 1H), 3.17 (dd, J=14.4, 9.2 Hz, 1H), 2.96 (m, 1H), 2.66 (m, 1H), 1.30(d, J=6.0 Hz, 3H), 1.11 (m, 12H). MS (ESI) m/z 427.4 (M+H⁺).

Example 95 H-Trp-Phe-OPropofol (203)

Following procedures for the preparation of compound and substitutingBoc-Ala-OH with Boc-Trp-OH provided the title compound (203). ¹H-NMR(400 MHz, CD₃OD): δ 7.63 (d, J=8.0 Hz, 1H), 7.34–7.00 (m, 12H), 5.13(dd, J=8.8, 6.0 Hz, 1H), 3.86 (dd, J=8.4, 4.4 Hz, 1H), 3.37 (dd, J=14.0,6.0 Hz, 1H), 3.07 (dd, J=13.6, 8.8 Hz, 1H), 2.99 (m, 2H), 2.69 (m, 1H),1.13 (m, 12H). MS (ESI) m/z 512.4 (M+H⁺).

Example 96 H-Tyr-Phe-OPropofol (204)

Following procedures for the preparation of compound H-Ala-Phe-OPropofoland substituting Boc-Ala-OH with Boc-Tyr-OH provided the title compound(204). ¹H-NMR (400 MHz, CD₃OD): δ 7.36–7.15 (m, 8H), 7.08 (d, J=8.0 Hz,2H), 6.72 (d, J=8.0 Hz, 2H), 5.15 (dd, J=10.0, 5.6 Hz, 1H), 3.94 (dd,J=9.2, 4.0 Hz, 1H), 3.49 (dd, J=14.0, 5.6 Hz, 1H), 3.18 (m, 2H), 2.98(m, 1H), 2.82 (dd, J=14.4, 8.8 Hz, 1H), 2.72 (m, 1H), 1.15 (m, 12H). MS(ESI) m/z 512.4 (M+H⁺).

Example 97 H-Val-Phe-OPropofol (205)

Following procedures for the preparation of compound H-Ala-Phe-OPropofoland substituting Boc-Ala-OH with Boc-Val-OH provided the title compound(205). ¹H-NMR (400 MHz, CD₃OD): δ 7.37–7.14 (m, 8H), 5.16 (dd, J=10.0,5.6 Hz, 1H), 3.59 (d, J=5.2 Hz, 1H), 3.44 (dd, J=14.0, 5.6 Hz, 1H), 3.13(dd, J=14.0, 9.6 Hz, 1H), 2.98 (m, 1H), 2.68 (m, 1H), 2.20 (m, 1H), 1.11(m, 12H), 1.07–0.98 (dd, J=29.6, 7.2 Hz, 6H). MS (ESI) m/z 425.4 (M+H⁺).

Example 98 H-Asp-Ser(β-OC(O)OPropofol)-OH (206)

Following procedures for the preparation of compound (161) andsubstituting Boc-Ala-OH with Boc-Asp(O^(t)Bu)-OH in Step A provided thetitle compound (206). ¹H-NMR (400 MHz, CD₃OD): δ 7.16 (m, 3H), 4.72 (dd,J=5.2, 3.6 Hz, 1H), 4.63 (dd, J=11.6, 5.6 Hz, 1H), 4.55 (dd, J=11.2, 3.2Hz, 1H), 4.21 (dd, J=10, 4 Hz, 1H), 2.99 (m, 3H), 2.70 (dd, J=17.6, 10Hz, 1H), 1.18 (d, J=7.2 Hz, 12H). MS (ESI) m/z (M+H⁺).

Example 99 H-Lys-Ser(β-OC(O)OPropofol)-OH (207)

Following procedures for the preparation of compound (161) andsubstituting Boc-Ala-OH with Boc-Lys(Boc)-OH in Step A provided thetitle compound (207). ¹H-NMR (400 MHz, CD₃OD): δ 7.16 (m, 3H), 4.65 (t,J=5.2 Hz, 1H), 4.56 (m, 2H), 3.92 (t, J=6.8 Hz, 1H), 2.97 (m, 4H),2.02–1.84 (m, 2H), 1.71–1.54 (m, 2H), 1.18 (d, J=7.2 Hz, 12H). MS (ESI)m/z (M+H⁺).

Example 100 H-Ser-Ser(β-OC(O)OPropofol)-OH (208)

Following procedures for the preparation of compound (161) andsubstituting Boc-Ala-OH with Boc-Ser(O^(t)Bu)-OH in Step A provided thetitle compound (208). ¹H-NMR (400 MHz, CD₃OD): δ 7.16 (m, 3H), 4.60 (m,3H), 3.95 (m, 3H), 2.99 (m, J=2H), 1.18 (d, J=7.2 Hz, 12H). MS (ESI) m/z397.7 (M+H⁺).

Example 101 H-Tyr-Ser(β-OC(O)OPropofol)-OH (209)

Following procedures for the preparation of compound (161) andsubstituting Boc-Ala-OH with Boc-Tyr-OH in Step A provided the titlecompound (209). ¹H-NMR (400 MHz, CD₃OD): δ 7.15 (m, 5H), 6.76 (d, J=8.8Hz, 2H), 4.58 (m, 3H), 4.08 (dd, 8.8, 4.8 Hz, 1H), 2.97 (m, 3H), 1.17(d, J=6.8 Hz, 12H). MS (ESI) m/z 473.7 (M+H⁺).

Example 102 H-Ala-Thr(β-OC(O)OPropofol)-OH (210)

Following procedures for the preparation of compound (161) andsubstituting Boc-Ser(O^(t)Bu)-OH with Boc-Thr(O^(t)Bu)-OH in Step Aprovided the title compound (210). ¹H-NMR (400 MHz, CD₃OD): δ 7.16 (m,3H), 4.49 (m, 1H), 4.09 (q, J=7.2 Hz, 1H), 2.95 (m, 2H), 1.57 (d, J=7.2Hz, 3H), 1.41 (d, J=6.4 Hz, 3H), 1.18 (dd, J=6.8 Hz, 1.6 Hz, 12H). MS(ESI) m/z 395.8 (M+H⁺).

Example 103 H-Asn-Thr(β-OC(O)OPropofol)-OH (211)

Following procedures for the preparation of compoundH-Ala-Thr(γ-OC(O)OPropofol)-OH and substituting Boc-Asn-OH forBoc-Ala-OH in Step A provided the title compound (211). ¹H-NMR (400 MHz,CD₃OD): δ 7.16 (m, 3H), 5.49 (m, 1H), 4.36 (dd, J=10, 3.6 Hz, 1H), 3.04(dd, J=17.2, 3.2 Hz, 1H), 2.94 (m, 2H), 2.78 (m, 11H), 1.41 (d, J=6.4Hz, 3H), 1.18 (dd, J=6.8 Hz, 1.6 Hz, 12H). MS (ESI) m/z 438.8 (M+H⁺).

Example 104 H-Lys-Thr(β-OC(O)OPropofol)-OH (212)

Following procedures for the preparation of compoundH-Ala-Thr(γ-OC(O)OPropofol)-OH and substituting Boc-Lys(Boc)-OH forBoc-Ala-OH in Step A provided the title compound (212). ¹H-NMR (400 MHz,CD₃OD): δ 7.17 (m, 3H), 5.50 (m, 1H), 4.09 (t, J=6.4 Hz, 1H), 2.94 (m,2H), 1.98 (m, 2H), 1.74 (m, 2H), 1.60 (m, 2H), 1.42 (d, J=6.4 Hz, 3H),1.18 (d, J=6.8 Hz, 12H). MS (ESI) m/z 452.9 (M+H⁺).

Example 105 H-Ser-Thr(β-OC(O)OPropofol)-OH (213)

Following procedures for the preparation of compoundH-Ala-Thr(γ-OC(O)OPropofol)-OH and substituting Boc-Ser(O^(t)Bu)-OH forBoc-Ala-OH in Step A provided the title compound (213). ¹H-NMR (400 MHz,CD₃OD): δ 7.16 (m, 31H), 5.49 (m, 1H), 4.11 (dd, J=6.8, 4 Hz, 1H), 3.87(dd, J=12.0, 7.2 Hz, 1H), 2.95 (m, 2H), 1.42 (d, J=6.4 Hz, 3H), 1.18 (d,J=6.8 Hz, 12H). MS (ESI) m/z 411.8 (M+H⁺).

Example 106 H-Val-Thr(β-OC(O)OPropofol)-OH (214)

Following procedures for the preparation of compoundH-Ala-Thr(γ-OC(O)OPropofol)-OH and substituting Boc-Val-OH forBoc-Ala-OH in Step A provided the title compound (214). ¹H-NMR (400 MHz,CD₃OD): δ 7.16 (m, 3H), 3.89 (d, J=5.6 Hz, 1H), 2.95 (m, 2H), 2.30 (m,1H), 1.42 (d, J=6.4 Hz, 3H), 1.18 (dd, J=6.8 Hz, 1.6 Hz, 12H), 1.12 (dd,J=20.4, 7.2 Hz, 6H). MS (ESI) m/z 423.8 (M+H⁺).

Example 107 H-Ala-Cys(β-SC(O)OPropofol)-OH (215) Step A:(Boc-Ala-Cys-O^(t)Bu)₂ (216)

To a mixture of cystine tert-butyl diester hydrochloride (0.5 g, 1.17mmol) and Boc-Ala-OH (0.45 g, 2.38 mmol) in DMF (8 mL) was addedO-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate(0.9 g, 237 mmol) followed by triethylamine (0.45 mL, 258 mmol). Theresulting reaction mixture was stirred for 14 h at room temperature, andthen diluted with 10% citric acid aqueous solution (20 mL) and ethylacetate (50 mL). The layers were separated and the organic layer waswashed with saturated NaHCO₃ aqueous solution (30 mL), brine (2×20 mL),dried over MgSO₄ and concentrated in vacuo. The crude residue waspurified by silica gel chromatography (hexane to 60% ethylacetate/hexane) to afford 0.77 g (93% yield) of the desired product(216).

Step B: Boc-Ala-Cys-O^(t)Bu (217)

To a solution of (216) (0.77 g, 1.1 mmol) in ethanol (3 mL) was addedindium powder (0.68 g, 5.9 mmol) and ammonium chloride (0.15 g, 2.86mmol). The resulting mixture was stirred under reflux for 14 h, thencooled to room temperature and filtered through a short plug of silicagel. The silica gel plug was washed with ethyl acetate and the filtratewas concentrated in vacuo. The crude product (217) was carried to thenext step without further purification.

Step C: H-Ala-Cys(β-SC(O)OPropofol)-OH (215)

To a cooled solution (0° C.) of crude (217) (0.5 g, 1.43 mmol) indichloromethane (4 mL) was added triethylamine (0.22 mL, 1.57 mmol)followed by 2,6-bis(isopropyl)phenoxycarbonyl chloride (163) (0.37 g,153 mmol). The resulting mixture was stirred at room temperature for 15h, and then diluted with 10% citric acid aqueous solution (10 mL) andethyl acetate (30 mL). The layers were separated and the organic layerwas washed with brine (30 mL), dried over MgSO₄ and concentrated invacuo. The crude residue was dissolved in dichloromethane (4 mL) andtreated with 4 N HCl in dioxane (3 mL), followed by trifluoroacetic acid(0.5 mL). The mixture was stirred at room temperature for 14 h thesolvent was removed in vacuo. The crude product was purified bypreparative LC/MS to afford the title compound (215) (128 mg, 22%yield). ¹H-NMR (400 MHz, CD₃OD): δ 7.21–7.14 (m, 3H), 4.49–4.46 (dd,J=7.6, 4.8 Hz, 1H), 3.88–3.86 (q, J=6.8 Hz, 1H), 3.64–3.59 (dd, J=13.6,4.8 Hz, 1H), 3.34–3.32 (m, 1H), 2.96 (m, 2H), 1.52 (d, J=6.8 Hz, 3H),1.19 (d, J=6.8 Hz, 6H), 1.17 (d, J=6.8 Hz, 6H). MS (ESI) m/z 397.77(M+H⁺).

Example 108 H-Lys-Cys(β-SC(O)OPropofol)-OH (218)

Following procedures for the preparation ofH-Ala-Cys(β-SC(O)OPropofol)-OH, and substituting Boc-Ala-OH withBoc-Lys(Boc)-OH, provided the title compound (218). ¹H-NMR (400 MHz,CD₃OD): δ 7.22–7.14 (m, 3H), 4.53–4.50 (dd, J=8.8, 4.8 Hz, 1H), 3.87 (t,J=6.0 Hz, 1H), 3.64–3.59 (dd, J=13.6, 4.8 Hz, 1H), 3.27–3.22 (dd,J=13.4, 8.4 Hz, 1H), 3.00–2.91 (m, 4H), 1.96–1.87 (m, 2H), 1.71–1.65 (m,2H), 1.59–1.52 (m, 2H), 1.19 (d, J=7.2 Hz, 6H), 1.17 (d, J=6.8 Hz, 6H).MS (ESI) m/z 454.85 (M+H⁺).

Example 109 H-Ser-Cys(β-SC(O)OPropofol)-OH (219)

Following procedures for the preparation ofH-Ala-Cys(β-SC(O)OPropofol)-OH, and substituting Boc-Ala-OH withBoc-Ser(O^(t)Bu)-OH, provided the title compound (219). ¹H-NMR (400 MHz,CD₃OD): δ 7.22–7.14 (m, 3H), 4.55–4.52 (dd, J=7.6, 4.4 Hz, 1H),3.91–3.87 (m, 3H), 3.66–3.62 (dd, J=13.6, 4.4 Hz, 1H), 3.32–3.26 (m,1H), 3.00–2.94 (m, 2H), 1.19 (d, J=6.8 Hz, 6H), 1.17 (d, J=6.8 Hz, 6H).MS (ESI) m/z 414.3 (M+H⁺).

Example 110 H-Asp-Asp(OCH₂OPropofol)-OH (220) Step A: PropofolChloromethyl Ether (221)

Propofol (5.5 mL, 30 mmol) was added to a suspension of sodium hydride(1.26 g, 31.5 mmol) in ethylene glycol dimethyl ether (30 mL) at 0° C.The suspension was stirred for 15 min. This mixture was then added to asolution of iodochloromethane (11.0 mL, 150 mmol) in ethylene glycoldimethyl ether (30 mL). The resulting mixture was stirred for 14 h atroom temperature and diluted with hexane. The organic solution was thenwashed with water, dried over magnesium sulfate and then concentrated invacuo. The crude compound was used without further purification. ¹H-NMR(400 MHz, CDCl₃): δ 7.1 (s, 3H), 5.17 (s, 2H), 3.35 (m, 2H), 1.16 (d,J=6.8 Hz, 12H)

Step B: Boc-Asp(OCH₂OPropofol)-OBn (222)

The above intermediate (2.26 g, 10 mmol) was mixed with the cesium saltof Boc-Asp-OBn (7.02 g, 15 mmol) in DMF (20 mL) and stirred for 14 h atroom temperature. The resulting solution was diluted with ether and theorganic solution was washed with 10% aqueous citric acid solution (2×30mL), and brine (2×30 mL). The organic layer was dried over magnesiumsulfate and then concentrated in vacuo. The crude compound was purifiedby chromatography on silica gel (Biotage), eluting with a gradient ofhexane to 10% EtOAc/hexane) then concentrated in vacuo (1.78 g, 34%yield). ¹H-NMR (400 MHz, CDCl₃): δ 7.30–7.31 (m, 5H), 7.07–7.11 (m, 3H)5.41–5.53 (m, 2H), 5.15 (s, 2H), 4.67 (m, 1H), 3.2–3.26 (m, 2H),3.07–3.08 (d, J=4.4 Hz, 1H), 2.88–2.90 (d, J=4.4 Hz, 11H), 2.84 (d,J=4.4 Hz, 1H), 1.42 (s, 9H), 1.2 (d, J=2.4 Hz, 6H), 1.18 (d, J=2.4 Hz,6H). MS (ESI) m/z 536.4 (M+Na⁺)

Step C: H-Asp(OCH₂OPropofol)-OBn (223)

The pure compound (1.78 g, 3.32 mmol) from above was dissolved indichloromethane (5 mL) and treated with trifluoroacetic acid (5 mL). Theresulting mixture was stirred at room temperature for 3 h. The solventwas removed in vacuo and the crude residue was carried to the next stepwithout further purification.

Step D: CBz-Asp(OBn)-Asp(OCH₂OPropofol)-OBn (224)

To a solution of above compound (0.45 g, 1 mmol) and Cbz-Asp(OBn)-OH(0.39 g, 1.1 mmol) in DMF (4 mL) was added diisopropylethylamine (0.56mL, 3.3 mmol) followed byO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluoro-phosphate(0.42 g, 1.1 mmol). The resulting mixture wasstirred at room temperature for 14 h and then diluted with 40 mL ofethyl acetate. The organic solution was washed with 10% aqueous citricacid solution (2×30 mL), saturated aqueous sodium bicarbonate solution(2×30 mL) and brine (2×30 mL). The organic layer was dried overmagnesium sulfate and then concentrated in vacuo. The crude compound(0.62 g) was used without further purification.

Step E: H-Asp-Asp(OCH₂OPropofol)-OH (220)

To a flask containing 50 mg of 10% Pd—C was added a solution of Asp-Asp(Obzl)-OCH₂OPropofol (0.62 g, 0.94 mmol) in methanol (5 mL) undernitrogen. The resulting mixture was degassed three times, after whichhydrogen was introduced via a balloon apparatus. The suspended mixturewas allowed to stir vigorously for 4 h. The reaction mixture wasfiltered through a pad of celite and concentrated in vacuo, thenpurified by preparative LC/MS to afford the title compound (42 mg, 10%yield). ¹H-NMR (400 MHz, CD₃OD): δ 7.09 (s, 3H), 5.53 (m, 2H), 4.67 (m,1H), 4.10 (m, 1H), 3.41 (dd, J=8.0, 16.4 Hz, 1H), 2.86–2.95 (m, 3H),1.19 (d, J=7.2 Hz, 12H). MS (ESI) m/z 439.8 (M+H⁺).

Example 111 H-Trp-Asp(OCH₂OPropofol)-OH (225)

Following procedures for the preparation of H-Asp-Asp(OCH₂OPropofol)-OH,and substituting Boc-Asp-OBn with Boc-Trp(Boc)-OH, provided the titlecompound (225). ¹H-NMR (400 MHz, CD₃OD): δ 7.6 (d, J=8.0 Hz, 1H), 7.33(d, J=8.0 Hz, 1H), 7.21 (s, 1H), 7.02–7.11 (m, 2H), 7.08 (m, 3H), 5.47(m, 2H), 4.53 (m, 1H), 4.13 (m, 1H), 3.4 (m, 2H), 3.24 (dd, J=8.0, 16.4Hz, 1H), 2.89 (m, 3H), 1.18 (d, J=7.4 Hz, 12H). MS (ESI) m/z510.8(M+H⁺).

Example 112 H-His-Asp(OCH₂OPropofol)-OH (226)

Following procedures for preparation of H-Asp-Asp(OCH₂OPropofol)-OH, andsubstituting Boc-Asp-OBn with Boc-His(Boc)-OH, provided the titlecompound (226). ¹H-NMR (400 MHz, CD₃OD): δ 8.35 (s, 1H), 8.09 (s, 2H),7.15 (s, 1H), 7.09 (s, 3H), 5.51–5.56 (m, 2H), 4.66–4.68 (m, 1H),4.10–4.13 (m, 1H), 3.28–3.24 (m, 2H), 2.99–3.05 (dd, J=4.8, 13.6 Hz,2H), 2.89 (dd, J=8.0, 16.0 Hz, 2H), 1.18 (d, J=7.2 Hz, 12H). MS (ESI)m/z 461.8 (M+H⁺).

Example 113 H-Asn-Asp(OCH₂OPropofol)-OH (227)

Following procedures for preparation of H-Asp-Asp(OCH₂OPropofol)-OH, andsubstituting Boc-Asp-OBn with Boc-Asn-OH, provided the title compound(227). ¹H-NMR (400 MHz, CD₃OD): δ 7.09 (s, 3H), 5.51 (s, 2H), 4.56–4.58(m, 1H), 4.14–4.18 (m, 1H), 3.28–3.24 (m, 2H), 2.93–2.98(m, 2H),2.85–2.89 (dd, J=4.8, 13.6 Hz, 1H), 2.68–2.75 (dd, J=8.0, 16.0 Hz, 2H),1.18 (d, J=7.2 Hz, 12H). MS (ESI) m/z 438.8 (M+H⁺).

Example 114 H-Gln-Asp(OCH₂OPropofol)-OH (228)

Following procedures for preparation of H-Asp-Asp(OCH₂OPropofol)-OH, andsubstituting Boc-Asp-OBn with Boc-Gln-OH, provided the title compound(228). ¹H-NMR (400 MHz, CD₃OD): δ 7.09 (s, 3H), 5.51 (s, 2H), 4.61 (m,1H), 3.89 (m, 1H), 3.46 (m, 2H), 2.84–2.98 (m, 2H), 2.46 (m, 2H), 2.11(m, 2H), 1.18 (d, J=7.2 Hz, 12H). MS (ESI) m/z 452.8(M+H⁺).

Example 115 H-Thr-Asp(OCH₂OPropofol)-OH (229)

Following procedures for preparation of H-Asp-Asp(OCH₂OPropofol)-OH, andsubstituting Boc-Asp-OBn with Boc-Thr(O^(t)Bu)-OH, provided the titlecompound (229). ¹H-NMR (400 MHz, CD₃OD): δ 7.09 (s, 3H), 5.51 (s, 2H),4.53 (m, 1H), 4.07 (m, 1H), 3.63 (d, J=5.6 Hz, 1H), 3.46 (m, 2H),2.84–2.98(m, 2H), 1.23(d, J=6.8 Hz, 3H), 1.18 (d, J=7.2 Hz, 12H). MS(ESI) m/z 425.3 (M+H⁺).

Example 116 H-Ser-Asp(OCH₂OPropofol)-OH (230)

Following procedures for preparation of H-Asp-Asp(OCH₂OPropofol)-OH, andsubstituting Boc-Asp-OBn with Boc-Ser(O^(t)Bu)-OH, provided the titlecompound (230). ¹H-NMR (400 MHz, CD₃OD): δ 7.09 (s, 3H), 5.51 (s, 2H),4.53 (m, 1H), 4.07 (m, 1H), 3.63 (d, J=5.6 Hz, 11H), 3.46 (m, 2H),2.84–2.98 (m, 2H), 1.18 (d, J=7.2 Hz, 12H). MS (ESI) m/z 411.8 (M+H⁺).

Example 117 H-Gly-Asp(OCH₂OPropofol)-OH (231)

Following procedures for preparation of H-Asp-Asp(OCH₂OPropofol)-OH, andsubstituting Boc-Asp-OBn with Boc-Gly-OH, provided the title compound(231). ¹H-NMR (400 MHz, CD₃OD): δ 7.09 (s, 3H), 5.51 (m, 2H), 4.61 (m,1H), 3.55–3.69 (m, 2H), 2.84–2.98 (m, 2H), 1.18 (d, J=7.2 Hz, 12H). MS(ESI) m/z 381.8 (M+H⁺).

Example 118 H-Glu-Asp(OCH₂OPropofol)-OH (232)

Following procedures for preparation of H-Asp-Asp(OCH₂OPropofol)-OH, andsubstituting Boc-Asp-OBn with Boc-Glu(O^(t)Bu)-OH, provided the titlecompound (232). ¹H-NMR (400 MHz, CD₃OD): δ 7.09 (s, 3H), 5.51 (m, 2H),4.61 (m, 1H), 3.91 (m, 1H), 3.34 (m, 2H), 2.92–2.97 (m, 2H), 2.51–2.54(m, 2H), 2.08–2.13 (m, 2H), 1.18 (d, J=7.2 Hz, 12H). MS (ESI) m/z 453.2(M+H⁺).

Example 119 H-Tyr-Asp(OCH₂OPropofol)-OH (233)

Following procedures for preparation of H-Asp-Asp(OCH₂OPropofol)-OH, andsubstituting Boc-Asp-OBn with Boc-Tyr-OH, provided the title compound(233). ¹H-NMR (400 MHz, CD₃OD): δ 7.09–7.11 (m, 5H), 6.73–6.75 (d, J=8.0Hz, 2H), 5.51 (m, 2H), 4.61 (m, 1H), 4.01 (m, 1H), 3.34 (m, 2H),2.92–2.97 (m, 2H) 1.18 (d, J=7.2 Hz, 12H). MS (ESI) m/z 487.3 (M+H⁺).

Example 120 H-Ala-Asp(OCH₂OPropofol)-OH (234)

Following procedures for preparation of H-Asp-Asp(OCH₂OPropofol)-OH, andsubstituting Boc-Asp-OBn with Boc-Ala-OH, provided the title compound(234). ¹H-NMR (400 MHz, CD₃OD): δ 7.09 (s, 3H), 5.52 (s, 2H), 4.55–4.52(dd, J=7.2, 4.8 Hz, 1H), 3.91 (q, J=6.8 Hz, 1H), 3.34–3.30 (m, 2H),2.98–2.94 (dd, J=16.4, 4.8 Hz, 1H), 2.89–2.83 (dd, J=16.4, 7.6 Hz, 1H),1.50 (d, J=7.2 Hz, 3H), 1.21 (d, J=7.2 Hz, 12H). MS (ESI) m/z 395.37(M+H⁺).

Example 121 H-Asp(OCH₂OPropofol)-Lys-OH (235) Step A:Boc-Asp(OCH₂OPropofol)-OH (236)

To a flask containing 50 mg of 10% Pd—C was added a solution ofBoc-Asp(OCH₂OPropofol)-OBn (0.77 g, 1.5 mmol) in methanol undernitrogen. The resulting mixture was degassed three times, after whichhydrogen was introduced via a balloon apparatus. The suspended mixturewas allowed to stir vigorously for 4 h at room temperature. The reactionmixture was filtered through a pad of celite and concentrated in vacuo.The crude compound (236) (0.64 g) was used without further purification.

Step B: Boc-Asp(OCH₂OPropofol)-Lys(Boc)-O^(t)Bu (237)

To a solution of (236) (0.64 g, 1.5 mmol) and H-Lys(Boc)-O^(t)Bu (0.557g, 1.65 mmol) in DMF was added diisopropylethylamine (0.51 mL, 3.0 mmol)followed by O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate(0.63 g, 1.65 mmol). The resulting mixture wasstirred at room temperature for 14 h and then diluted with ethyl acetate(40 mL). The organic solution was washed with 10% aqueous citric acidsolution (2×30 mL), saturated aqueous sodium bicarbonate solution (2×30mL) and brine (2×30 mL). The organic layer was dried over magnesiumsulfate and then concentrated in vacuo. The crude compound (237) wasused without further purification.

Step C: H-Asp(OCH₂OPropofol)-Lys-OH (235)

Compound (237) (0.65 g, 0.92 mmol) from above was dissolved indichloromethane (1.5 mL) and treated with trifluoroacetic acid (1.5 mL).The resulting mixture was stirred at room temperature for 3 h. Thesolvent was removed in vacuo and the crude residue was purified bypreparative LC/MS to afford the title compound (235). ¹H-NMR (400 MHz,CD₃OD): δ 7.09 (s, 3H), 5.51 (s, 2H), 4.23 (m, 1H), 4.07 (m, 1H),2.79–3.02 (m, 4H), 1.81 (m, 2H), 1.62–1.78 (m, 4H), 1.45 (m, 2H), 1.18(d, J=7.2 Hz, 12H). MS (ESI) m/z 452.8(M+H⁺).

Example 122 H-Asp(OCH₂OPropofol)-Asp-OH (238)

Following procedures for preparation of H-Asp(OCH₂OPropofol)-Lys, andsubstituting H-Lys(Boc)-O^(t)Bu with H-Asp(O^(t)Bu)—O^(t)Bu, providedthe title compound (238). ¹H-NMR (400 MHz, CD₃OD): δ 7.11 (s, 3H), 5.62(s, 2H), 4.59–4.56 (m, 1H), 4.22–4.19 (dd, J=9.2, 4.0 Hz, 1H), 3.18–3.13(dd, J=17.6, 4.0 Hz, 1H), 2.93–2.72 (m, 5H), 1.21 (d, J=6.4 Hz, 12H). MS(ESI) m/z 439.27 (M+H⁺).

Example 123 H-Asp(OCH₂OPropofol)-Arg-OH (239)

Following procedures for preparation of H-Asp(OCH₂OPropofol)-Lys, andsubstituting H-Lys(Boc)-O^(t)Bu with H-Arg(Pmc)-O^(t)Bu, provided thetitle compound (239). ¹H-NMR (400 MHz, CD₃OD): δ 7.11 (s, 3H), 5.62–5.59(ABq, J=7.2, 5.6 Hz, 2H), 4.25 (t, J=6.0 Hz, 1H), 4.14 (m, 1H),3.34–3.31 (m, 2H), 3.18 (t, J=6.8 Hz, 2H), 3.14–3.09 (dd, J=17.6, 4.0Hz, 1H), 2.91–2.84 (dd, J=17.2, 8.4 Hz, 1H), 1.89–1.86 (m, 1H),1.77–1.63 (m, 3H), 1.21 (d, J=6.4 Hz, 12H). MS (ESI) m/z 480.28 (M+H⁺).

Example 124 H-Asp(OCH₂OPropofol)-Ser-OH (240)

Following procedures for preparation of H-Asp(OCH₂OPropofol)-Lys, andsubstituting H-Lys(Boc)-O^(t)Bu with H-Ser(O^(t)Bu)-O^(t)Bu, providedthe title compound (240). ¹H-NMR (400 MHz, CD₃OD): δ 7.11 (s, 3H), 5.62(s, 2H), 4.39 (t, J=4.8 Hz, 1H), 4.27–4.24 (dd, J=9.2, 4.4 Hz, 1H), 3.86(d, J=4.8 Hz, 2H), 3.35–3.31 (m, 2H), 3.21–3.16 (dd, J=17.6, 4.4 Hz,1H), 2.93–2.86 (dd, J=18.0, 9.2 Hz, 1H), 1.21 (d, J=6.4 Hz, 12H). MS(ESI) m/z 411.31 (M+H⁺).

Example 125 H-Val-OCH₂OPropofol (241) Step A: Boc-Val-O⁻Cs⁺ (242)

To a solution of Boc-Val-OH (1.0 g, 4.6 mmol) in a 1:4 mixture ofacetonitrile:H₂O (5 mL) was added cesium bicarbonate (0.9 g, 4.6 mmol).The resulting solution was stirred for 10 min, and then the solvent wasfrozen and lyophilized to give (242) as a white powder.

Step B: H-Val-OCH₂OPropofol (241)

To a solution of propofol chloromethyl ether (221) (0.36 g, 1.59 mmol)in DMF (4 mL) was added (242) (0.5 g, 1.42 mmol). The resulting reactionmixture was stirred at room temperature for overnight, then diluted withethyl acetate (30 mL) and 10% citric acid aqueous solution (20 mL). Thelayers were separated and the organic layer was washed with brine (2×20mL), dried over MgSO₄ and concentrated in vacuo. The crude residue wasdissolved in dichloromethane (4 mL) and treated with trifluoroaceticacid (1 mL). The reaction was stirred for 3 h at room temperature. Thesolvent was removed in vacuo, and the crude product purified bypreparative LC/MS to afford the title compound (241) (118 mg, 27%yield). ¹H-NMR (400 MHz, CD₃OD): δ 7.12–7.08 (m, 3H), 5.63–5.58 (Abq,J=16, 5.2 Hz, 2H), 3.58 (d, J=3.6 Hz, 1H), 3.32–3.25 (m, 2H), 2.24–2.19(m, 1H), 1.21 (d, J=6.8 Hz, 12H), 1.05 (d, J=6.8 Hz, 3H), 0.96 (d, J=6.8Hz, 3H). MS (ESI) m/z 308.43 (M+H⁺).

Example 126 H-Aib-OCH₂OPropofol (243)

Following procedures for preparation of H-Val-OCH₂OPropofol, andsubstituting Boc-Val-OH with Boc-Aib-OH, provided the title compound(243). ¹H-NMR (400 MHz, CD₃OD): δ 7.12–7.08 (m, 3H), 5.60 (s, 2H),3.32–3.25 (m, 2H), 1.49 (s, 6H), 1.21 (d, J=6.8 Hz, 12H). MS (ESI) m/z294.39 (M+H⁺).

Example 127 H-Asp(OCH₂OPropofol)-OH (244)

Following procedures for preparation of H-Val-OCH₂OPropofol, andsubstituting Boc-Val-OH with Boc-Asp-O^(t)Bu, provided the titlecompound (244). ¹H-NMR (400 MHz, CD₃OD): δ 7.11 (s, 3H), 5.63–5.57 (Abq,J=21.6, 5.6 Hz, 2H), 3.95–3.92 (dd, J=8.4, 3.6 Hz, 1H), 3.34–3.29 (m,2H), 3.14–3.08 (dd, J=18.4, 4.0 Hz, 1H), 2.93–2.86 (dd, J=18.4, 8.8 Hz,1H), 1.21 (d, J=6.8 Hz, 12H). MS (ESI) m/z 324.34 (M+H⁺).

Example 128 H-Asp-OCH₂OPropofol (245)

Following procedures for preparation of H-Val-OCH₂OPropofol, andsubstituting Boc-Val-OH with Boc-Asp(O^(t)Bu)-OH, provided the titlecompound (245). ¹H-NMR (400 MHz, CD₃OD): δ 7.11 (s, 3H), 5.63–5.68 (Abq,J=89.6, 5.6 Hz, 2H), 4.17 (t, J=5.2 Hz, 1H), 3.31 (m, 2H), 2.82 (d,J=5.6 Hz, 2H), 1.21 (d, J=7.2 Hz, 12H). MS (ESI) m/z 324.34 (M+H⁺).

Example 129 H-Dap(β-NHC(O)OPropofol)-Ala-OH (246) Step A:Cbz-Dap(Boc)-Ala-OBn (247)

Cbz-Dap(Boc)-OH (0.41 g, 1.2 mmol) was treated with a mixture of1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide methiodide (0.374 g,1.26 mmol) and N-hydroxybenzotriazole (0.17 g, 1.26 mmol) inN-methylmorpholine (0.28 mL, 2.1 mmol) in dichloromethane. H-Ala-OBn(0.26 g, 1.2 mmol) was added to the above solution and the resultingmixture was stirred for 14 h at room temperature, then diluted withethyl acetate (40 mL). The organic solution was washed with 10% aqueouscitric acid solution (2×30 mL), saturated aqueous sodium bicarbonatesolution (2×30 mL) and brine (2×30 mL). The organic layer was dried overmagnesium sulfate and then concentrated in vacuo. The crude compound(247) (0.51 g) was used without further purification.

Step B: Cbz-Dap-Ala-OBn (248)

Compound (247) (0.51 g, 1.02 mmol) from above was dissolved indichloromethane (1 mL) and treated with trifluoroacetic acid (1 mL). Theresulting mixture was stirred at room temperature for 3 h. The solventwas removed in vacuo and the crude residue (248) (0.49 g) was used inthe next step without further purification.

Step C: CBz-Dap(β-NHC(O)OPropofol)-Ala-OBn (249)

To an ice cold solution of chloroformate (163) (0.384 g, 1.6 mmol) indichloromethane (4 mL) was added triethylamine (0.075 mL, 1.3 mmol)followed by compound (248) (0.4 g, 1 mmol). The resulting mixture wasallowed to warm to room temperature and stirred for 12 h. The mixturewas diluted with ethyl acetate (30 mL) and washed with 10% aqueouscitric acid solution (2×30 mL), dried over MgSO₄, filtered andconcentrated in vacuo. The crude product (249) (0.66 g) was used in thenext step without further purification.

Step D: H-Dap(β-NHC(O)OPropofol)-Ala-OH (246)

To a flask containing 50 mg of 10% Pd—C was added a solution of compound(249) (0.66 g, 1 mmol) in methanol (5 mL) under nitrogen. The resultingmixture was degassed three times, after which hydrogen was introducedvia a balloon apparatus. The suspended mixture was allowed to stirvigorously for 4 h. The reaction mixture was filtered through a pad ofcelite and concentrated in vacuo and the crude residue was purified bypreparative LC/MS to afford the title compound (246) (48 mg, 13% yield).¹H-NMR (400 MHz, CD₃OD): δ 7.11–7.17 (m, 3H), 4.47 (m, 1H), 4.23 (q,1H), 3.31 (m, 2H), 3.01 (m, 2H), 1.38 (d, J=7.2 Hz, 3H), 1.17 (d, J=7.4Hz, 12H). MS (ESI) m/z 380.3 (M+H⁺).

Example 130 H-Lys-Glu(OPropofol)-OH (250)

Following procedures for preparation of compound (107) and substitutingCBz-Lys(CBz)-OH for CBz-Ala-OH and compound (105) for compound (102)provided the title compound (250). ¹H-NMR (400 MHz, CD₃OD): δ 7.17 (m,3H), 4.31 (dd, J=8.4, 5.2 Hz, 11H), 3.90 (dd, J=7.6, 6.0 Hz, 1H), 2.89(m, 4H), 2.77 (t, J=8.4 Hz, 2H), 2.34 (m, 1H), 2.10 (m, 1H), 1.89 (m,2H), 1.76–1.50 (m, 4H), 1.18 (d, J=6.8 Hz, 12H). MS (ESI) m/z 437.43(M+H⁺).

Example 131 In Vitro Compound Transport Assays: Analysis of ElectrogenicTransport in PEPT1-Expressing Xenopus Oocytes

Transport-induced currents were also measured in Xenopus oocytestransfected with rat and human PEPT1 as described in PCT ApplicationWO01/20331. Briefly:

RNA preparation: Rat and human PEPT1 transporter cDNAs were subclonedinto a modified pGEM plasmid that contains 5′ and 3′ untranslatedsequences from the Xenopus β-actin gene. These sequences increase RNAstability and protein expression. Plasmid cDNA was linearized and usedas template for in vitro transcription (Epicentre Technologiestranscription kit, 4:1 methylated:non-methylated GTP).

Xenopus oocyte isolation. Xenopus laevis frogs were anesthetized byimmersion in Tricaine (1.5 g/mL in deionized water) for 15 min. Oocyteswere removed and digested in frog ringer solution (90 mM NaCl, 2 mM KCl,1 mM MgCl₂, 10 mM NaHEPES, pH 7.45, no CaCl₂) with 1 mg/mL collagenase(Worthington Type 3) for 80–100 min with shaking. The oocytes werewashed 6 times, and the buffer changed to frog ringer solutioncontaining CaCl₂ (1.8 mM). Remaining follicle cells were removed ifnecessary. Cells were incubated at 16° C., and each oocyte injected with10–20 μg RNA in 45 μL solution.

Electrophysiology measurements. Transport currents were measured 2–14days after injection, using a standard two-electrode electrophysiologyset-up (Geneclamp 500 amplifier, Digidata 1320/PCLAMP software andADInstruments hardware and software were used for signal acquisition).Electrodes (2–4 mΩ) were microfabricated using a Sutter Instrumentpuller and filled with 3M KCl. The bath was directly grounded(transporter currents were less than 0.3 μA). Bath flow was controlledby an automated perfusion system (ALA Scientific Instruments, solenoidvalves).

For transporter pharmacology, oocytes were clamped at −60 to −90 mV, andcontinuous current measurements acquired using PowerLab Software and anADInstruments digitizer. Current signals were lowpass filtered at 20 Hzand acquired at 4–8 Hz. All bath and drug-containing solutions were frogringers solution containing CaCl₂. Drugs were applied for 10–30 secondsuntil the induced current reached a new steady-state level, followed bya control solution until baseline currents returned to levels thatpreceded drug application. The difference current (baseline subtractedfrom peak current during drug application) reflected the net movement ofcharge resulting from electrogenic transport and was directlyproportional to transport rate. Recordings were made from a singleoocyte for up to 60 min, enabling 30–40 separate compounds to be testedper oocyte. Compound-induced currents were saturable and gavehalf-maximal values at substrate concentrations comparable to radiolabelcompetition experiments. To compare results between oocytes expressingdifferent levels of transport activity, a saturating concentration ofglycyl-sarcosine (1 mM) was used as a common reference to normalizeresults from test compounds. Using this normalization procedure I_(max)(i.e. maximal induced current) for different compounds tested ondifferent oocytes could be compared.

Each of the compounds (107), (115), (116), (119)–(122), (124), (136),(138)–(140), (143), (145)–(150), (161), (208), (210), (213), (220),(227)–(229), (241), (243) and (250) elicited PEPT-specific currentssignificantly above background (at least 2% Of I_(max) for Gly-Sar) whentested at 3 mM on oocytes expressing PEPT1, confirming that thesecompounds serve as substrates for this transporter.

Example 132 Standard Methods for Determination of Enzymatic Cleavage ofProdrugs In Vitro

The stability of propofol prodrugs were evaluated in one or more invitro systems using a variety of tissue preparations following methodsknown in the art. Tissues were obtained from commercial sources (e.g.,Pel-Freez Biologicals, Rogers, Ark., or GenTest Corporation, Woburn,Mass.). Experimental conditions used for the in vitro studies aredescribed in Table 1 below. Each preparation was incubated with testcompound at 37° C. for one hour. Aliquots (50 μL) were removed at 0, 30,and 60 min and quenched with 0.1% trifluoroacetic acid in acetonitrile.Samples were then centrifuged and analyzed by LC/MS/MS (see Examples 59and 60 below for method details). Stability of drug conjugates towardsspecific enzymes (e.g., peptidases, etc.) were also assessed in vitro byincubation with the purified enzyme:

Aminopeptidase Stability: Aminopeptidase 1 (Sigma catalog # A-9934) wasdiluted in deionised water to a concentration of 856 units/mL. Stabilitystudies were conducted by incubating conjugate (5 μM) with 0.856units/mL aminopeptidase 1 in 50 mM Tris-HCl buffer at pH 8.0 and 37° C.Concentrations of intact conjugate and released drug were determined atzero time and 60 minutes using LC/MS/MS.

Pancreatin Stability: Stability studies were conducted by incubatingconjugate (5 μM) with 1% (w/v) pancreatin (Sigma, P-1625, from porcinepancreas) in 0.025 M Tris buffer containing 0.5 M NaCl (pH 7.5) at 37°C. for 60 min. The reaction was stopped by addition of 2 volumes ofmethanol. After centrifugation at 14,000 rpm for 10 min, the supernatantwas removed and analyzed by LC/MS/MS.

Caco-2 Homogenate S9 Stability: Caco-2 cells were grown for 21 daysprior to harvesting. Culture medium was removed and cell monolayers wererinsed and scraped off into ice-cold 10 mM sodium phosphate/0.15 Mpotassium chloride, pH 7.4. Cells were lysed by sonication at 4° C.using a probe sonicator. Lysed cells were then transferred into 1.5 mLcentrifuge vials and centrifuged at 9000 g for 20 min at 4° C. Theresulting supernatant (Caco-2 cell homogenate S9 fraction) was aliquotedinto 0.5 mL vials and stored at −80° C. until used.

For stability studies, prodrug (5 μM) was incubated in Caco-2 homogenateS9 fraction (0.5 mg protein per mL) for 60 min at 37° C. Concentrationsof intact prodrug and released propofol were determined at zero time and60 minutes using LC/MS/MS.

Preferred conjugates demonstrate at least 1% cleavage to produce thefree drug or an active metabolite thereof within a 60 minute period, assummarized in Table 2.

TABLE 1 Standard Conditions for Conjugate In Vitro Metabolism StudiesSubstrate Preparation Concentration Cofactors Rat Plasma 2.0 μM NoneHuman Plasma 2.0 μM None Rat Liver S9 2.0 μM NADPH (0.5 mg/mL) HumanLiver S9 2.0 μM NADPH (0.5 mg/mL) Human Intestine 2.0 μM NADPH S9 (0.5mg/mL) Carboxypeptidase A 2.0 μM None (10 units/mL) Caco-2 5.0 μM NoneHomogenate Pancreatin 5.0 μM None Aminopeptidase 5.0 μM None * NADPHgenerating system, e.g., 1.3 mM NADP+, 3.3 mM glucose-6-phosphate, 0.4U/mL glucose-6-phosphate dehydrogenase, 3.3 mM magnesium chloride and0.95 mg/mL potassium phosphate, pH 7.4.

TABLE 2 % of Propofol Released from Propofol Prodrugs after 60 min. inVarious Tissue Preparations (107) (121) (122) (124) (138) (152) (161)(192) (208) (220) (250) Rat Plasma 3 7 2 65 50 37 30 15 ND ND 79 HumanPlasma 1 3 0 2 44 0 2 15 2 1 17 Rat Liver S9 6 0 9 0 0 11 8 60 ND ND 36(0.5 mg/mL) Human Liver S9 5 0 6 0 0 8 14 60 3 0 34 (0.5 mg/mL) Caco-2S9 4 0 0 0 3 6 20 41 21 49 19 Pancreatin 7 0 10 4 9 1 8 0 25 6 0 ND—Notdone

Example 133 Uptake of Propofol Following Oral Administration to RatsStep A: Administration Protocol

Propofol was administered as an intravenous bolus injection or by oralgavage to groups of four to six adult male Sprague-Dawley rats (weightapprox 250 g) as solutions in PEG400, at doses of 10 mg per kg bodyweight (I.V.) or 25 mg per kg body weight (oral). Animals were fastedovernight before the study and for 4 hours post-dosing. Blood samples(1.0 mL) were obtained via a jugular vein cannula at intervals over 24hours after oral dosing. Blood was quenched immediately usingacetonitrile with 1% formic acid and then was frozen at −80° C. untilanalyzed.

Step B: LC/MS/MS Analysis

Concentrations of propofol in plasma were determined using an API 4000LC/MS/MS instrument equipped with an Agilent 1100 binary pump and anAgilent autosampler. The column was a Phenomenex Hydro-RP 4.6*50 mmcolumn operating at room temperature. The mobile phases were 2 mMaqueous ammonium acetate (A) and 95% acetonitrile with 5 mM ammoniumacetate (B). The gradient condition was: 5% B for 1 min, increasing to90% B in 2.5 min and maintained for 2 min. 20 μL of sample was injected.A Turbo-IonSpray source was used, and propofol was detected in negativeion mode in Q1 at m/z=177. The peaks were integrated using Analyst 1.2quantitation software.

The oral bioavailability (F) of propofol, determined by comparison ofthe area under the propofol concentration versus time curve (AUC)following oral administration with the AUC measured followingintravenous propofol administration, was found to be very low asexpected (F=0.23%).

Example 134 Uptake of Propofol Following Oral Administration of Prodrugsto Rats Step A: Administration Protocol

Test compounds were administered by oral gavage or as an intravenousbolus injection to groups of four to six adult male Sprague-Dawley rats(weight approx 250 g) as solutions in PEG400 at a dose of 25mg-equivalents of propofol per kg body weight. Animals were fastedovernight before the study and for 4 hours post-dosing. Blood samples(1.0 mL) were obtained via a jugular vein cannula at intervals over 24hours after oral dosing. Blood was quenched immediately usingacetonitrile with 1% formic acid and then was frozen at −80° C. untilanalyzed.

Step B: LC/MS/MS Analysis

Concentrations of propofol in whole blood were determined using an API4000 LC/MS/MS instrument as described above. For determination of theprodrug concentrations in whole blood, the mobile phases were 0.1%formic acid (A) and acetonitrile with 0.1% formic acid (B). The gradientcondition was: 5% B for 1 min, increasing to 90% B in 2.5 min andmaintained for 2 min. 101 L of sample was injected. A TurboIonSpraysource was used and the prodrugs were detected in positive ion mode,using MRM transitions of 365/294 for (107), 457/136 for (122), 422/136for (124), 422/136 for (124), and 436/84 for (250). The peaks wereintegrated using Analyst 1.2 quantitation software.

Oral bioavailability (F) of the prodrugs as propofol were determined bycomparison of the areas under the propofol concentration versus timecurves (AUC) following oral administration of the prodrugs with the AUCmeasured following intravenous administration of propofol itself on adose-normalized basis. Each of the compounds (107), (122), (124) and(250) showed substantial oral bioavailabilities as propofol (F>50%)illustrating that actively transported prodrugs can afford dramaticenhancements (>200-fold) in oral bioavailability of propofol.

Example 135 Uptake of Propofol Following Oral Administration of Prodrugsto Monkeys Step A: Administration Protocol

Test compounds were administered by oral gavage or as an intravenousbolus injection to groups of two to four adult male Cynomologous (Macacafascicularis) monkeys (weight approx 5 kg) as solutions in water orPEG400 at a dose of 25 mg-equivalents of propofol per kg body weight.Animals were fasted overnight before the study and for 4 hourspost-dosing. Blood samples (1.0 mL) were obtained via the femoral veinat intervals over 24 hours after oral dosing. Blood was quenchedimmediately using acetonitrile with 1% formic acid and then was frozenat −80° C. until analyzed. Test compounds are administered in themonkeys with a minimum of 72 hour wash out period between dosingsessions.

Step B: LC/MS/MS Analysis

Concentrations of propofol in whole blood were determined using an API4000 LC/MS/MS instrument as described above and the prodrugs weredetected in positive ion mode, using MRM transitions of 365/294 for(107), 457/136 for (122), 422/136 for (124), 422.19/136.08 for (124),423/405 for (140), 436/84 for (146), 381/159 for (161), 399/136 for(192), 436/207 for (201), 397/175 for (208), 411/189 for (213), 439/261for (220), and 436/84 for (250). The peaks were integrated using Analyst1.2 quantitation software.

Oral bioavailability (F) of the prodrugs as propofol in monkeys weredetermined by comparison of the areas under the propofol concentrationversus time curves (AUC) following oral administration of the prodrugswith the AUC measured following intravenous administration of propofolitself on a dose-normalized basis.

The compounds (174), (213) and (250) had oral bioavailabilities aspropofol >10%, while (140), (146) and (208) had oral bioavailabilitiesas propofol >40%, illustrating that actively transported prodrugs canafford significant enhancements in oral bioavailability of propofol.

Finally, it should be noted that there are alternative ways ofimplementing the present invention. Accordingly, the present embodimentsare to be considered as illustrative and not restrictive, and theinvention is not to be limited to the details given herein, but may bemodified within the scope and equivalents of the claim(s) issuingherefrom. All publications and patents cited herein are incorporated byreference.

1. A compound of Formula (I):

or a pharmaceutically acceptable salt, hydrate, solvate or n-oxidethereof, wherein: X is selected from the group consisting of a bond,CH₂, NR¹¹, O and S; m is 1 or 2; n is 0 or 1; R¹ is selected from thegroup consisting of hydrogen, [R⁵NH(CHR⁴)_(p)C(O)]—, R⁶—, R⁶C(O)— andR⁶OC(O)—; R² is —OR⁷ or —[NR⁸(CHR⁹)_(q)C(O)OR⁷]; p and q areindependently 1 or 2; R³ is selected from the group consisting ofhydrogen, alkyl, substituted alkyl, alkoxycarbonyl, aryl, substitutedaryl, arylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, heteroaryl, substitutedheteroaryl and heteroarylalkyl; each R⁴ is independently selected fromthe group consisting of hydrogen, alkyl, substituted alkyl, alkoxy,substituted alkoxy, acyl, substituted acyl, alkoxycarbonyl, substitutedalkoxycarbonyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl, substitutedcycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl,substituted heteroalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl and substituted heteroarylalkyl, or optionally, when R⁴and R⁵ are attached to adjacent atoms then R⁴ and R⁵ together with theatoms to which they are bonded form a cycloheteroalkyl or substitutedcycloheteroalkyl ring; R⁵ is selected from the group consisting ofhydrogen, R⁶—, R⁶C(O)— and R⁶C(O)—; R⁶ is selected from the groupconsisting of alkyl, substituted alkyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, heteroaryl, substituted heteroaryl andheteroarylalkyl; R⁷ is selected from the group consisting of hydrogen,alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,heteroaryl, substituted heteroaryl and heteroarylalkyl; R⁸ is selectedfrom the group consisting of hydrogen, alkyl, substituted alkyl, aryl,substituted aryl, arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, heteroaryl, substituted heteroaryl andheteroarylalkyl; each R⁹ is independently selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, alkoxy, substitutedalkoxy, acyl, substituted acyl, alkoxycarbonyl, substitutedalkoxycarbonyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl, substitutedcycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl,substituted heteroalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl and substituted heteroarylalkyl, or optionally, when R⁸and R⁹ are attached to adjacent atoms then R⁸ and R⁹ together with theatoms to which they are bonded form a cycloheteroalkyl or substitutedcycloheteroalkyl ring; R¹¹ is selected from the group consisting ofhydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl,cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, heteroaryl,substituted heteroaryl and heteroarylalkyl; with the provisos that: whenR¹ is [R⁵NH(CHR⁴)_(p)C(O)]-then R² is —OR⁷; and when R² is—[NR⁸(CHR⁹)_(q)C(O)OR⁷] then R¹ is not [R⁵NH(CHR⁴)_(p)C(O)]—.
 2. Thecompound of claim 1, wherein n is
 0. 3. The compound of claim 1 havingstructural Formula (III):

wherein R⁴ is selected from the group consisting of hydrogen, alkanyl,substituted alkanyl, aryl, substituted aryl, arylalkanyl, substitutedarylalkanyl, cycloalkanyl, heteroarylalkanyl and substitutedheteroarylalkanyl.
 4. The compound of claim 3, wherein R⁴ is selectedfrom the group consisting of hydrogen, methyl, isopropyl, isobutyl,sec-butyl, t-butyl, cyclopentyl, cyclohexyl, —CH₂OH, —CH(OH)CH₃,—CH₂CO₂H, —CH₂CH₂CO₂H, —CH₂CONH₂, —CH₂CH₂CONH₂, —CH₂CH₂SCH₃, —CH₂SH,—CH₂(CH₂)₃NH2, —CH₂CH₂CH₂NHC(NH)NH₂, phenyl, benzyl, 4-hydroxybenzyl,4-imidazolylmethyl and 3-indolylmethyl.
 5. The compound of claim 1having structural Formula (IV):

wherein R⁴ is selected from the group consisting of hydrogen, alkanyl,substituted alkanyl, aryl, substituted aryl, arylalkanyl, substitutedarylalkanyl, cycloalkanyl, heteroarylalkanyl and substitutedheteroarylalkanyl.
 6. The compound of claim 5, wherein R⁴ is selectedfrom the group consisting of hydrogen, methyl, isopropyl, isobutyl,sec-butyl, t-butyl, cyclopentyl, cyclohexyl, —CH₂OH, —CH(OH)CH₃,—CH₂CO₂H, —CH₂CH₂CO₂H, —CH₂CONH₂, —CH₂CH₂CONH₂, —CH₂CH₂SCH₃, —CH₂SH,—CH₂(CH₂)₃NH₂, —CH₂CH₂CH₂NHC(NH)NH₂, phenyl, benzyl, 4-hydroxybenzyl,4-imidazolylmethyl and 3-indolylmethyl.
 7. The compound of claim 1having structural Formula (V):

wherein R⁴ is selected from the group consisting of hydrogen, alkanyl,substituted alkanyl, aryl, substituted aryl, arylalkanyl, substitutedarylalkanyl, cycloalkanyl, heteroarylalkanyl and substitutedheteroarylalkanyl.
 8. The compound of claim 7, wherein R⁴ is selectedfrom the group consisting of hydrogen, methyl, isopropyl, isobutyl,sec-butyl, t-butyl, cyclopentyl, cyclohexyl, —CH₂OH, —CH(OH)CH₃,—CH₂CO₂H, —CH₂CH₂CO₂H, —CH₂CONH₂, —CH₂CH₂CONH₂, —CH₂CH₂SCH₃, —CH₂SH,—CH₂(CH₂)₃NH₂, —CH₂CH₂CH₂NHC(NH)NH₂, phenyl, benzyl, 4-hydroxybenzyl,4-imidazolylmethyl and 3-indolylmethyl.
 9. The compound of claim 1having structural Formula (VI):

wherein R⁴ is selected from the group consisting of hydrogen, alkanyl,substituted alkanyl, aryl, substituted aryl, arylalkanyl, substitutedarylalkanyl, cycloalkanyl, heteroarylalkanyl and substitutedheteroarylalkanyl.
 10. The compound of claim 9, wherein R⁴ is selectedfrom the group consisting of hydrogen, methyl, isopropyl, isobutyl,sec-butyl, t-butyl, cyclopentyl, cyclohexyl, —CH₂OH, —CH(OH)CH₃,—CH₂CO₂H, —CH₂CH₂CO₂H, —CH₂CONH₂, —CH₂CH₂CONH₂, —CH₂CH₂SCH₃, —CH₂SH,—CH₂(CH₂)₃NH₂, —CH₂CH₂CH₂NHC(NH)NH₂, phenyl, benzyl, 4-hydroxybenzyl,4-imidazolylmethyl and 3-indolylmethyl.
 11. The compound of claim 1having structural Formula (VII):

wherein R³ is hydrogen or methyl; and R⁴ is selected from the groupconsisting of hydrogen, alkanyl, substituted alkanyl, aryl, substitutedaryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl,heteroarylalkanyl and substituted heteroarylalkanyl.
 12. The compound ofclaim 11, wherein R⁴ is selected from the group consisting of hydrogen,methyl, isopropyl, isobutyl, sec-butyl, t-butyl, cyclopentyl,cyclohexyl, —CH₂OH, —CH(OH)CH₃, —CH₂CO₂H, —CH₂CH₂CO₂H, —CH₂CONH₂,—CH₂CH₂CONH₂, —CH₂CH₂SCH₃, —CH₂SH, —CH₂(CH₂)₃NH₂, —CH₂CH₂CH₂NHC(NH)NH₂,phenyl, benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl and 3-indolylmethyl.13. A compound of Formula (VIII):

wherein R³ is hydrogen or methyl; and R⁴ is selected from the groupconsisting of hydrogen, alkanyl, substituted alkanyl, aryl, substitutedaryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl,heteroarylalkanyl and substituted heteroarylalkanyl.
 14. The compound ofclaim 13, wherein R⁴ is selected from the group consisting of hydrogen,methyl, isopropyl, isobutyl, sec-butyl, t-butyl, cyclopentyl,cyclohexyl, —CH₂OH, —CH(OH)CH₃, —CH₂CO₂H, —CH₂CH₂CO₂H, —CH₂CONH₂,—CH₂CH₂CONH₂, —CH₂CH₂SCH₃, —CH₂SH, —CH₂(CH₂)₃NH₂, —CH₂CH₂CH₂NHC(NH)NH₂,phenyl, benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl and 3-indolylmethyl.15. The compound of claim 1 having structural Formula (IX):

wherein R⁸ is hydrogen or methyl; and R⁹ is selected from the groupconsisting of hydrogen, alkanyl, substituted alkanyl, aryl, substitutedaryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl,heteroarylalkanyl and substituted heteroarylalkanyl, or optionally R⁸and R⁹ together with the atoms to which they are bonded form acycloheteroalkyl or substituted cycloheteroalkyl ring.
 16. The compoundof claim 15, wherein R⁸ is hydrogen and R⁹ is selected from the groupconsisting of hydrogen, methyl, isopropyl, isobutyl, sec-butyl, t-butyl,cyclopentyl, cyclohexyl, —CH₂OH, —CH(OH)CH₃, —CH₂CO₂H, —CH₂CH₂CO₂H,—CH₂CONH₂, —CH₂CH₂CONH₂, —CH₂CH₂SCH₃, —CH₂SH, —CH₂(CH₂)₃NH₂,—CH₂CH₂CH₂NHC(NH)NH₂, phenyl, benzyl, 4-hydroxybenzyl,4-imidazolylmethyl and 3-indolylmethyl.
 17. The compound of claim 15,wherein R⁸ and R⁹ together with the atoms to which they are bonded forman azetidine, pyrrolidine or piperidine ring.
 18. The compound of claim1 having structural Formula (X):

wherein R⁸ is hydrogen or methyl; and R⁹ is selected from the groupconsisting of hydrogen, alkanyl, substituted alkanyl, aryl, substitutedaryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl,heteroarylalkanyl and substituted heteroarylalkanyl, or optionally R⁸and R⁹ together with the atoms to which they are bonded form acycloheteroalkyl or substituted cycloheteroalkyl ring.
 19. The compoundof claim 18, wherein R⁸ is hydrogen and R⁹ is selected from the groupconsisting of hydrogen, methyl, isopropyl, isobutyl, sec-butyl, t-butyl,cyclopentyl, cyclohexyl, —CH₂OH, —CH(OH)CH₃, —CH₂CO₂H, —CH₂CH₂CO₂H,—CH₂CONH₂, —CH₂CH₂CONH₂, —CH₂CH₂SCH₃, —CH₂SH, —CH₂(CH₂)₃NH₂,—CH₂CH₂CH₂NHC(NH)NH₂, phenyl, benzyl, 4-hydroxybenzyl,4-imidazolylmethyl and 3-indolylmethyl.
 20. The compound of claim 19,wherein R⁸ and R⁹ together with the atoms to which they are bonded forman azetidine, pyrrolidine or piperidine ring.
 21. The compound of claim1 having structural Formula (XI):

wherein R³ is hydrogen or methyl; R⁸ is hydrogen or methyl; and R⁹ isselected from the group consisting of hydrogen, alkanyl, substitutedalkanyl, aryl, substituted aryl, arylalkanyl, substituted arylalkanyl,cycloalkanyl, heteroarylalkanyl and substituted heteroarylalkanyl, oroptionally R⁸ and R⁹ together with the atoms to which they are bondedform a cycloheteroalkyl or substituted cycloheteroalkyl ring.
 22. Thecompound of claim 21, wherein R³ is hydrogen.
 23. The compound of claim22, wherein R⁸ is hydrogen and R⁹ is selected from the group consistingof hydrogen, methyl, isopropyl, isobutyl, sec-butyl, t-butyl,cyclopentyl, cyclohexyl, —CH₂OH, —CH(OH)CH₃, —CH₂CO₂H, —CH₂CH₂CO₂H,—CH₂CONH₂, —CH₂CH₂CONH₂, —CH₂CH₂SCH₃, —CH₂SH, —CH₂(CH₂)₃NH₂,—CH₂CH₂CH₂NHC(NH)NH₂, phenyl, benzyl, 4-hydroxybenzyl,4-imidazolylmethyl and 3-indolylmethyl.
 24. The compound of claim 22,wherein R⁸ and R⁹ together with the atoms to which they are bonded forman azetidine, pyrrolidine or piperidine ring.
 25. The compound of claim1 having structural Formula (XII):


26. The compound of claim 1 having structural Formula (XIII):


27. The compound of claim 1 having structural Formula (XIV):

wherein R³ is hydrogen or methyl.
 28. The compound of claim 1 havingFormula (XV):

wherein R³ is hydrogen or methyl.
 29. A compound of Formula (II):

or a pharmaceutically acceptable salt, hydrate, solvate or N-oxidethereof, wherein: n is 0 or 1; R¹⁰ is hydrogen or [R⁵NH(CHR⁴)_(p)C(O)]—;p and q are independently 1 or 2; R³ is selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, aryl,substituted aryl, arylalkyl, carbamoyl, substituted carbamoyl,cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, heteroaryl,substituted heteroaryl and heteroarylalkyl; each R⁴ is independentlyselected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkoxy, substituted alkoxy, acyl, substituted acyl,alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, carbamoyl, substituted carbamoyl,cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substitutedcycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl,substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl,or optionally, when R⁴ and R⁵ are attached to adjacent atoms then R⁴ andR⁵ together with the atoms to which they are bonded form acycloheteroalkyl or substituted cycloheteroalkyl ring; R⁵ is selectedfrom the group consisting of hydrogen, R⁶—, R⁶C(O)— and R¹⁰C(O)—; R⁶ isselected from the group consisting of alkyl, substituted alkyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, heteroaryl, substitutedheteroaryl and heteroarylalkyl; R⁸ is selected from the group consistingof hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,heteroaryl, substituted heteroaryl and heteroarylalkyl; each R⁹ isindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkoxy, substituted alkoxy, acyl, substituted acyl,alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, carbamoyl, substituted carbamoyl,cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substitutedcycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl,substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl,or optionally, when R⁸ and R⁹ are attached to adjacent atoms then R⁸ andR⁹ together with the atoms to which they are bonded form acycloheteroalkyl or substituted cycloheteroalkyl ring; with the provisothat: when R¹⁰ is hydrogen then n is
 1. 30. The compound of claim 29,wherein n is
 0. 31. The compound of claim 29 having structural Formula(XVI):

wherein R⁴ is selected from the group consisting of hydrogen, alkanyl,substituted alkanyl, aryl, substituted aryl, arylalkanyl, substitutedarylalkanyl, cycloalkanyl, heteroarylalkanyl and substitutedheteroarylalkanyl; R⁸ is hydrogen or methyl; and R⁹ is selected from thegroup consisting of hydrogen, alkanyl, substituted alkanyl, aryl,substituted aryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl,heteroarylalkanyl and substituted heteroarylalkanyl, or optionally, R⁸and R⁹ together with the atoms to which they are bonded form acycloheteroalkyl or substituted cycloheteroalkyl ring.
 32. The compoundof claim 31, wherein R⁸ is hydrogen and R⁹ is selected from the groupconsisting of hydrogen, methyl, isopropyl, isobutyl, sec-butyl, t-butyl,cyclopentyl, cyclohexyl, —CH₂OH, —CH(OH)CH₃, —CH₂CO₂H, —CH₂CH₂CO₂H,—CH₂CONH₂, —CH₂CH₂CONH₂, —CH₂CH₂SCH₃, —CH₂SH, —CH₂(CH₂)₃NH₂,—CH₂CH₂CH₂NHC(NH)NH₂, phenyl, benzyl, 4-hydroxybenzyl,4-imidazolylmethyl and 3-indolylmethyl.
 33. The compound of claim 31,wherein R⁸ and R⁹ together with the atoms to which they are bonded forman azetidine, pyrrolidine or piperidine ring.
 34. The compound of claim31, wherein R⁴ is selected from the group consisting of hydrogen,methyl, isopropyl, isobutyl, sec-butyl, t-butyl, cyclopentyl,cyclohexyl, —CH₂OH, —CH(OH)CH₃, —CH₂CO₂H, —CH₂CH₂CO₂H, —CH₂CONH₂,—CH₂CH₂CONH₂, —CH₂CH₂SCH₃, —CH₂SH, —CH₂(CH₂)₃NH₂, —CH₂CH₂CH₂NHC(NH)NH₂,phenyl, benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl and 3-indolylmethyl.35. The compound of claim 32 or 33, wherein both the N— and C-terminalamino acid residues are of the L-configuration.
 36. The compound ofclaim 35, wherein R⁹ is hydrogen, R⁹ is methyl and R⁴ is selected fromthe group consisting of hydrogen, methyl, isopropyl, isobutyl,sec-butyl, t-butyl, cyclopentyl, cyclohexyl, —CH₂OH, —CH(OH)CH₃,—CH₂CO₂H, —CH₂CH₂CO₂H, —CH₂CONH₂, —CH₂CH₂CONH₂, —CH₂CH₂SCH₃, —CH₂SH,—CH₂(CH₂)₃NH₂, —CH₂CH₂CH₂NHC(NH)NH₂, phenyl, benzyl, 4-hydroxybenzyl,4-imidazolylmethyl and 3-indolylmethyl.
 37. The compound of claim 35,wherein R⁸ is hydrogen, R⁹ is —CH₂CONH₂ and R⁴ is selected from thegroup consisting of hydrogen, methyl, isopropyl, isobutyl, sec-butyl,t-butyl, cyclopentyl, cyclohexyl, —CH₂OH, —CH(OH)CH₃, —CH₂CO₂H,—CH₂CH₂CO₂H, —CH₂CONH₂, —CH₂CH₂CONH₂, —CH₂CH₂SCH₃, —CH₂SH,—CH₂(CH₂)₃NH₂, —CH₂CH₂CH₂NHC(NH)NH₂, phenyl, benzyl, 4-hydroxybenzyl,4-imidazolylmethyl and 3-indolylmethyl.
 38. The compound of claim 35,wherein R⁸ is hydrogen, R⁹ is benzyl and R⁴ is selected from the groupconsisting of hydrogen, methyl, isopropyl, isobutyl, sec-butyl, t-butyl,cyclopentyl, cyclohexyl, —CH₂OH, —CH(OH)CH₃, —CH₂CO₂H, —CH₂CH₂CO₂H,—CH₂CONH₂, —CH₂CH₂CONH₂, —CH₂CH₂SCH₃, —CH₂SH, —CH₂(CH₂)₃NH₂,—CH₂CH₂CH₂NHC(NH)NH₂, phenyl, benzyl, 4-hydroxybenzyl,4-imidazolylmethyl and 3-indolylmethyl.
 39. The compound of claim 35,wherein R⁸ is hydrogen, R⁹ is 4-hydroxybenzyl and R⁴ is selected fromthe group consisting of hydrogen, methyl, isopropyl, isobutyl,sec-butyl, t-butyl, cyclopentyl, cyclohexyl, —CH₂OH, —CH(OH)CH₃,—CH₂CO₂H, —CH₂CH₂CO₂H, —CH₂CONH₂, —CH₂CH₂CONH₂, —CH₂CH₂SCH₃, —CH₂SH,—CH₂(CH₂)₃NH₂, —CH₂CH₂CH₂NHC(NH)NH₂, phenyl, benzyl, 4-hydroxybenzyl,4-imidazolylmethyl and 3-indolylmethyl.
 40. The compound of claim 29having structural Formula (XVII):

wherein R³ is hydrogen or methyl; R⁹ is hydrogen or methyl; and R⁹ isselected from the group consisting of hydrogen, alkanyl, substitutedalkanyl, aryl, substituted aryl, arylalkanyl, substituted arylalkanyl,cycloalkanyl, heteroarylalkanyl and substituted heteroarylalkanyl, oroptionally R⁸ and R⁹ together with the atoms to which they are bondedform a cycloheteroalkyl or substituted cycloheteroalkyl ring.
 41. Thecompound of claim 40, wherein R⁸ is hydrogen and R⁹ is selected from thegroup consisting of hydrogen, methyl, isopropyl, isobutyl, sec-butyl,t-butyl, cyclopentyl, cyclohexyl, —CH₂OH, —CH(OH)CH₃, —CH₂CO₂H,—CH₂CH₂CO₂H, —CH₂CONH₂, —CH₂CH₂CONH₂, —CH₂CH₂SCH₃, —CH₂SH,—CH₂(CH₂)₃NH₂, —CH₂CH₂CH₂NHC(NH)NH₂, phenyl, benzyl, 4-hydroxybenzyl,4-imidazolylmethyl and 3-indolylmethyl.
 42. The compound of claim 40,wherein R⁸ and R⁹ together with the atoms to which they are bonded forman azetidine, pyrrolidine or piperidine ring.
 43. The compound of claim29 having structural Formula (XVIII):

wherein R³ is hydrogen or methyl; R⁴ is selected from the groupconsisting of hydrogen, alkanyl, substituted alkanyl, aryl, substitutedaryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl,heteroarylalkanyl and substituted heteroarylalkanyl; R⁸ is hydrogen ormethyl; and R⁹ is selected from the group consisting of hydrogen,alkanyl, substituted alkanyl, aryl, substituted aryl, arylalkanyl,substituted arylalkanyl, cycloalkanyl, heteroarylalkanyl and substitutedheteroarylalkanyl, or optionally, R⁸ and R⁹ together with the atoms towhich they are bonded form a cycloheteroalkyl or substitutedcycloheteroalkyl ring.
 44. The compound of claim 43, wherein R⁸ ishydrogen and R⁹ is selected from the group consisting of hydrogen,methyl, isopropyl, isobutyl, sec-butyl, t-butyl, cyclopentyl,cyclohexyl, —CH₂OH, —CH(OH)CH₃, —CH₂CO₂H, —CH₂CH₂CO₂H, —CH₂CONH₂,—CH₂CH₂CONH₂, —CH₂CH₂SCH₃, —CH₂SH, —CH₂(CH₂)₃NH₂, —CH₂CH₂CH₂NHC(NH)NH₂,phenyl, benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl and 3-indolylmethyl.45. The compound of claim 43, wherein R⁸ and R⁹ together with the atomsto which they are bonded form an azetidine, pyrrolidine or piperidinering.
 46. The compound of claim 44 or 45, wherein R⁴ is selected fromthe group consisting of hydrogen, methyl, isopropyl, isobutyl,sec-butyl, t-butyl, cyclopentyl, cyclohexyl, —CH₂OH, —CH(OH)CH₃,—CH₂CO₂H, —CH₂CH₂CO₂H, —CH₂CONH₂, —CH₂CH₂CONH₂, —CH₂CH₂SCH₃, —CH₂SH,—CH₂(CH₂)₃NH₂, —CH₂CH₂CH₂NHC(NH)NH₂, phenyl, benzyl, 4-hydroxybenzyl,4-imidazolylmethyl and 3-indolylmethyl.
 47. A method for treating orreducing risk of acquiring migraine, nausea, vomiting, anxiety,seizures, convulsions, trauma of the central nervous system, andneurodegenerative conditions selected from the group consisting ofFriedrich's disease, Parkinson's disease, Alzheimer's disease,Huntington's disease, amyotrophic lateral sclerosis (ALS), multiplesclerosis (MS) and Pick disease in a patient, comprising administeringto a patient in need of such treatment or reduction in risk atherapeutically effective amount of a compound according to claim 1 or29.
 48. A pharmaceutical composition comprising a therapeuticallyeffective amount of a compound according to claim 1 or 29 and apharmaceutically acceptable vehicle.